AU2005285812B2 - Aminoalcohol derivatives - Google Patents

Description

WO 2006/033446 PCT/JP2005/017669 DESCRIPTION AMINOALCOHOL DERIVATIVES 5 FIELD OF THE INVENTION This invention relates to new aminoalcohol derivatives and salts thereof which are beta-3 ( 3) adrenergic receptor agonists and useful as a medicament. 10 BACKGROUND OF THE INVENTION International Publication No. WO 90/06299, published June 14, 1990, describes derivatives of phenylethanolamines as having an effect on the metabolism, preferably reduction of the blood sugar level and body fat, 15 International Publication No. WO 02/32897, published April 25, 2002, describes derivatives of alpha-aryl ethanolamines useful as P3 adrenergic receptor agonists, and, International Publication Nos. WO 2004/002939, published January 8, 2004, and WO 2005/061433, published 20 July 7, 2005, describe aminoalcohol derivatives useful as P3 adrenergic receptor agonist. DISCLOSURE OF THE INVENTION This invention relates to new aminoalcohol 25 derivatives which are P3 adrenergic receptor agonists and salts thereof. More particularly, it relates to new aminoalcohol derivatives and salts thereof which are useful for the treatment and/or prevention of gastro-intestinal disorders, 30 ulcer, overactive bladder, micturition disorders, pancreatitis, obesity, diabetes, etc., to processes for the preparation thereof, to a pharmaceutical composition comprising the same and to a method of using the same therapeutically in the treatment and/or prevention of the 35 aforesaid disorders in a human being or an animal.

2 In one aspect, this invention advantageously provides new ana useful aminoalcohol derivatives and salts thereof which are useful for- the treatment and/or prevention of the aforesaid .disorders. 5 In another aspect, this invention advantageously provides processes .for the preparation of said aminoalcohol derivatives and salts thereof. In a further aspect, this invention advantageously provides a pharmaceutical composition comprising, as an active 10 ingredient, said aminoalcohol derivatives .and salts thereof. In another aspect, this invention advantageously provides a therapeutical method for the treatment and/or prevention of the aforesaid diseases in a human being or an animal, 15 using said aminoalcohol derivatives and salts thereof. The object aminoalcohol derivatives of this invention are new and can be represented by compound of the following formula [I]: 20- OH R3 R1 N R 7

AX

R8

R

2 25. wherein is or \A/ 30 G is - or R6 -X- is / ,in which -Y- is bond, -0-, -NH

R

4

R

5 35 WO 2006/033446 PCT/JP2005/017669 3 or -CH 2 -, and

R

4 , R 5 and R 6 are each independently hydrogen, lower alkyl or hydroxy(lower)alkyl, or 5 I , in which n is 0, 1 or 2;

(CH

2 n RI is hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, aryloxy, nitro, amino, (mono or di) (lower) 10 alkylamino or arylamino, R2 is hydrogen, lower alkyl or hydroxy(lower)alkyl, R3 is hydrogen or an amino protective group, R7 is hydrogen, lower alkyl, cyclo(lower)alkyl, lower R9 15 alkenyl, -Z-R 9 or -N , in which -Z- is -0-, -S-, R9 -SO- or -S02-, and each R 9 is independently hydrogen, lower alkyl, cyclo(lower)alkyl, lower alkenyl, 20 carbamoyl, lower alkylcarbamoyl, lower alkylsulfonyl, aryl or a heterocyclic group, and

R

8 is -D--E-R 10 , in which -D- is -CONHSO 2 - or -SO 2 NHCO-, E is bond or lower alkylene, and 25 R10 is halogen, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, a heterocyclic group,

-O-R

11 , -S-R 1 1 or N , in which R11 30 each R11 is independently hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or aryl(lower)alkyl, 35 or a prodrug thereof or a salt thereof.

WO 2006/033446 PCT/JP2005/017669 4 According to this invention, the object compounds can be prepared by processes which are illustrated in the following schemes. 5 Process 1

R

3 + HN R7 R CH-CH / I\AZ I\ R2 R . 10 [I or a salt thereof OH R 3 N R""A NX-GR 15 R8 R2 [II] or a salt thereof 20 Process 2 OH Ra 3 R N R/ R'A'II X---G R R8 25

R

2 [Ia] or a salt thereof elimination reaction of the OH H 30 the amino protective group R1 N R7 A) X-G R8 R 2 [Ib] 35 or a salt thereof WO 2006/033446 PCT/JP2005/017669 5 Process 3 OH R3 R N R 5 A X-Y1 + (HO) 2 B--G/ R8

R

2 [IV] [V] or a salt thereof or a salt thereof 10 OH R3 A X--G

R

2 R8 15 [Ic] or a salt thereof Process 4 OH R3 20 R1 N0 R7 A X-Y1 + B-G R2

R

8 25 [IV] [VI] or a salt thereof or a salt thereof OH R 3 R Ni R7 30 R2 [Ic] 35 or a salt thereof WO 2006/033446 PCT/JP2005/017669 6 Process 5 OH Ra 3 RI N \/R7 5 A X--G Ay -G\ 12 COOR R2 [Id] or a salt thereof 10 OH Ra 3 deesterification reaction R1 N R7 A/y X-G COOH R2 15 [Ie] or a salt thereof

H

2

NSO

2

-E-R

0 OH Ra 3 20 [VII] a or a salt thereof R N /R

CONHSO

2

-E-R

10 R2 [If] 25 or a salt thereof Process 6 OH Ras 30 R1 N R7 A X--G + HOOC-E-R 0

SO

2

NH

2 R2 [IX] [VIII] or a salt thereof 35 or a salt thereof WO 2006/033446 PCT/JP2005/017669 7 OH Ra 3

R

1

R

7 5 A /X-G

SO

2 NHCO-E-R'o . R2 [Ig] or a salt thereof 10 whereinA , -X-, R 1 , R 2 , R 3 , R 7 , R 8 , E and R are each as defined above, 15 R3 is an amino protective group, R12 is lower alkyl, and Yl is a leaving group. As to the starting compounds [II], [III], [Ia], [IV], 20 [V], [VI], [Id], [VIII] and [IX], some of them are novel and can be prepared by the procedures described in the Preparations and Examples mentioned below or a conventional manner. 25 In the above and subsequent description of the present specification, suitable examples of the various definition to be included within the scope of the invention are explained in detail in the following. 30 The term "lower" is intended to mean a group having 1 to 8, preferably 1 to 7, more preferably 1 to 6, most preferably 1 to 4, carbon atom(s), unless otherwise indicated. 35 Suitable "lower alkyl" and "lower alkyl" moiety in WO 2006/033446 PCT/JP2005/017669 8 the terms of "hydroxy(lower)alkyl", "(mono or di)(lower) alkylamino", "lower alkylcarbamoyl)", "lower alkylsulfonyl" and "aryl(lower)alkyl" may include straight .or branched one having 1 to 8, preferably 1 to 7, more 5 preferably 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, 1-methylpentyl, tert-pentyl, neo-pentyl, hexyl, isohexyl, and the like, in which preferable one may be methyl, ethyl, propyl, isopropyl or isobutyl. 10 Suitable "lower alkoxy" and "lower alkoxy" moiety in the term of "lower alkoxycarbonyl" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, tert butoxy, pentyloxy, tert-pentyloxy, hexyloxy, and the like, 15 in which preferable one may be methoxy or tert-butoxy. Suitable "lower alkanoyl" may include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2 dimethylpropanoyl, hexanoyl, and the like, in which 20 preferable one may be acetyl. Suitable "cyclo(lower)alkyl" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, in which preferable one may be 25 cyclo(C 3

-C

7 )alkyl, and more preferable one may be cyclopentyl, cyclohexyl or cycloheptyl. Suitable "lower alkenyl" may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1-(or 2- or 3- or 30 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)hexenyl, 1-(or 2-)methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1-(or 2-)propenyl, 1-(or 2- or 3-)ethyl-1-(or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which preferable one may be C 2

-C

4 alkenyl. 35 WO 2006/033446 PCT/JP2005/017669 9 Suitable "lower alkylene" may include straight or branched alkylene having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, 2,2-dimethyltri 5 methylene, 3,3-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene and propylene, in which preferable one may be straight alkylene having 1 to 4 carbon atoms. 10 Suitable "halogen" may be fluoro, chloro, bromo and iodo, in which preferable one may be fluoro or chloro. Suitable "aryl" and "aryl" moiety in the terms of "aryloxy", "arylamino" and "aryl(lower)alkyl" may include 15 phenyl, naphthyl, indenyl, anthryl, and the like, in which preferable one may be phenyl. Suitable "heterocyclic group" may be one containing at least one hetero atom selected from nitrogen, sulfur 20 and oxygen atom, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and preferable heterocyclic group may be N-containing heterocyclic group such as unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, 25 for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl., pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3 triazolyl, etc.], tetrazolyl [e.g. 1H-tetrazolyl, 2H tetrazolyl, etc.],. etc.; 30 saturated 3 to 7-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [e.g.. pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 5 35 nitrogen atoms, for example, indolyl, isoindolyl, WO 2006/033446 PCT/JP2005/017669 10 indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g. tetrazolo[1,5-b]pyridazinyl, etc.], quioxalinyl, etc.; 5 unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; saturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, 1H 10 tetrahydropyranyl, tetrahydrofuranyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, for example, thienyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group 15 containing 1 to 2 'oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], oxazolinyl [e.g. 2-oxazolinyl, etc.], etc.; saturated 3 to 6-membered heteromonocyclic group 20 containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzofurazanyl, benzoxazolyl, benzoxadiazolyl, etc.]; 25 unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g. 1,2,4 thiadiazolyl, 1,3 ,4-thiadiazolyl, 1,2, 5-thiadiazolyl, etc.], etc.; 30 saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. thiazolidinyl, etc.]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. 35 benzothiazolyl, benzothiadiazolyl, etc.]; WO 2006/033446 PCT/JP2005/017669 11 unsaturated condensed heterocyclic group containing 1 -to 2 oxygen atoms [e.g. benzofuranyl, benzodioxolyl, chromanyl, etc.], and the like.. 5 Suitable "leaving group" may include hydroxy, reactive group derived from hydroxy, and the like. Suitable "reactive group derived from hydroxy" may include acid residue and the like. Suitable "acid residue" may include halogen [e.g. 10 fluoro, chloro, bromo, iodo], acyloxy [e.g. acetoxy, tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, etc.], and the like. Suitable example of "amino protective group" may be 15 common amino protective group such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert amyloxycarbonyl, etc.], substituted or unsubstituted 20 aralkyloxycarbonyl [e.g. benzyloxycarbonyl, p-nitro benzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g. benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, aryl(lower)alkyl [e.g. trityl, benzyl, etc.], and the like, in which preferable one is tert 25 butoxycarbonyl. Suitable salts of the object aminoalcohol derivative [I] are pharmaceutically acceptable salts and include conventional non-toxic salts such as an inorganic acid' 30 addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], an alkali metal 35 salt [e.g. sodium salt, potassium salt, etc.], and the WO 2006/033446 PCT/JP2005/017669 12 like, in which preferable one is hydrochloride. The Processes 1 to 6 for preparing the object compounds of the present invention are explained in detail 5 in the following. Process 1 The object compound [I] or a salt thereof can be prepared by reacting a compound [II] with a compound [III] 10 or a salt thereof. Suitable salt of the compound [III] may be the same as those exemplified for the compound .[I]. The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate-[e.g. sodium 15 carbonate, potassium carbonate, etc.], an alkaline earth metal carbonate [e.g. magnesium carbonate, calcium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], tri(lower)alkylamine [e.g. trimethylamine, triethylamine, 20 etc.], picoline, and the like. The reaction is usually carried out in a conventional solvent, such as an alcohol [e.g. methanol, ethanol, propanol, isopropanol, etc.], diethyl ether,' tetrahydrofuran, dioxane, or any other organic solvent 25 which does not adversely influence the reaction. The reaction temperature is not critical, and the reaction can be carried out under c3oling to heating. Process 2 30 The object compound [Ib] or a salt thereof can be prepared by subjecting a compound [Ia] or a salt thereof to elimination reaction of the amino protective group. Suitable salts of the compounds [Ia] and [Ib] may be the same as those exemplified for the compound [I]. 35 This reaction can be carried out in a similar manner WO 2006/033446 PCT/JP2005/017669 13 to that of Example 3 mentioned below. Process 3 The object compound [Ic] or a salt thereof can be 5 prepared by reacting a compound [IV] or a salt thereof with a compound [V) or a salt thereof. Suitable salts of the compounds [Ic], [IV] and [V] may be the same as those exemplified for the compound [I]. This reaction can be carried out in a similar manner 10 to that of Example 2 mentioned below. Process 4 The object compound [Ic] or a salt thereof can be prepared by reacting a compound [IV] or a salt thereof with 15 a compound [VI] or a salt thereof. Suitable salts of the compounds [Ic], [IV] and [VI] may be the same as those exemplified for the compound [I]. This reaction can be carried out in a similar manner to that of Preparation 43 mentioned below. 20 Process 5 The object compound [If] or a salt thereof can be prepared by subjecting a compound [Id] or a salt thereof to deesterification reaction followed by reacting the 25 resulting compound [Ie] or a salt thereof with a compound [VII] or a salt thereof. Suitable salts of the compounds [If], [Id], [Ie] and [VII] may be the same as those exemplified for the compound [I]. 30 These reactions can be carried out in a similar manner to that of Preparation 3 and Example 11 mentioned below. Process 6 The object compound [Ig] or a slat thereof can be 35 prepared by reacting a compound [VIII] or a salt thereof WO 2006/033446 PCT/JP2005/017669 14 with a compound [IX] or a salt thereof. Suitable salt of the compounds [Ig], [VIII] and [IX] may be the same as those exemplified for the compound [I]. This reaction can be carried out in a similar manner 5 to that of Example 18 mentioned bellow. The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, 10 reprecipitation, and the like, and converted to the desired salt in conventional manners, if necessary. It is to be noted that the compound [I] and the other compounds may include one or more stereoisomers due to asymmetric carbon atoms, and all of such isomers and 15 mixture thereof are included within 'the scope of this invention. It is further to be noted that isomerization or rearrangement of the object compound [I] may occur due to the effect of the light, acid base or the like, and the 20 compound obtained as the result of said isomerization or rearrangement if also included within the scope of the present invention. It is also to be noted that the solvating form of the compound [I] [e.g. hydrate, etc.] and any form of the 25 crystal of the compound [I] are included within the scope of the present invention. The object compound [I] or a salt thereof are useful for the treatment and/or prevention 'of gastro-intestinal 30 disorders in human beings or animals, and more particularly for the treatment and/or prevention of spasm or hyperanakinesia in case of irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystopathy, cholantitis, urinary calculus, and the 35 .like; for the treatment and/or prevention of ulcer such as WO 2006/033446 PCT/JP2005/017669 15 gastric ulcer, duodenal ulcer, peptic ulcer, and the like; for the treatment and/or prevention of overactive bladder such as nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, 5- chronic cystitis, chronic prostatitis, prostatic hypertrophy, and the like; for the treatment and/or prevention of micturition disorders such as stress incontinence, urge incontinence, mixed incontinence, functional incontinence, overflow incontinence, and the 10 like; for the treatment and/or prevention of pancreatitis, obesity, diabetes, glycosuria, hyperlipidemia', hypertension, atherosclerosis, glaucoma, melancholia, depression, and the like; for the treatment and/or prevention of diseases as the result of insulin resistance. 15 [e.g. hypertension, hyperinsulinemia, etc.); for the treatment and/or prevention of neurogenetic inflammation; and for reducing a wasting condition, and the like. Additionally, P3 adrenergic receptor agonists are known to lower triglyceride and cholesterol levels and to 20 raise high density lipoprotein levels in mammals (US Patent No. 5,451,677). Accordingly, the object compound [I] is useful in the treatment and/or prevention of conditions such as hyper-triglyceridaemia, hypercholesterolaemia and in lowering high density 25 lipoprotein levels as well as in the treatment of atherosclerotic and cardiovascular diseases and relates conditions. Moreover, the object compound [I] is useful for inhibiting uterine contractions, preventing premature 30 labor, and treating and preventing dysmenorrhea. Additionally, the object compound [I] may be expected, when used together with an anticholinergic agent for overactive bladder such as propiverine hydrochloride, 35 oxybutinin hydrochloride, flavoxate hydrochloride, 16 tolterodine tartrate, and the like, to exert an enhanced anti-overactive-bladder effect. For therapeutic purpose, the compound (I) and a 5 pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an -active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid 10 or liquid excipient suitable for oral, parenteral, external including topical, internal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration. The pharmaceutical preparations may be solid, semi-solid 15 or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, and the like. If desired, there may be included 20 in these preparations, auxiliary substances, stabilizing . Sgehnis, wetting or emulsifying agents, buffers and other commonly used additives. While the dosage of the compound (I) will vary depending upon the age and condition of a patient, an 25 average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating diseases such as ulcer, overactive bladder, micturition disorders, and the like. In general, amounts between 0.1 mg/body and about 1,000 30 mg/body may be administered per day.

C.\NRPonb\DCCUXT3440663 .LDOC-3 110 V2011 - 16A In another aspect, there is provided a pharmaceutical composition which comprises, as an active ingredient, the compound (I) or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients. In a further aspect, there is provided a use of the compound (I) or a 5 pharmaceutically acceptable salt thereof for the manufacture of a medicament. In another aspect, there is provided a use of the compound (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylactic and/or the therapeutic treatment of gastro-intestinal disorders, ulcer, overactive bladder, micturition disorders, pancreatitis, obesity or diabetes. 10 In a further aspect, there is provided a method for the prophylactic and/or the therapeutic treatment of gastro-intestinal disorders, ulcer, overactive bladder, micturition disorders, pancreatitis, obesity or diabetes which comprises administering the compound (I) or a pharmaceutically acceptable salt thereof to a human being or an animal. 15 In order to show the usefulness of the compound [I] for the prophylactic and therapeutic treatment of above-mentioned disease in human being or animals, a representative compound of the compound [I] was tested on WO 2006/033446 PCT/JP2005/017669 17 the following pharmaceutical test. Test Effect on the increase in intravesical pressure 5 induced by carbachol in anesthetized dog Test compound (1) 3-(Cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4'-[2 [[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4 10 biphenylcarboxamide hydrochloride (the object compound of Example 1-(8) mentioned below) Test Method Female Beagle dogs weighing 8.0-15.0 kg were fasted 15 for 24 hours and maintained under halothane anesthesia. A- 12F Foley catheter was lubricated with water soluble jelly, inserted into the urethral orifice .and advanced approximately 10 cm until the'balloon tip was placed well inside the bladder. The balloon was then inflated with 5 20 ml of room air and catheter slowly withdrawn just part the first resistance that was felt at the bladder neck. Urine was completely drained out through the catheter, and 30 ml of biological saline was infused. The catheter was connected to pressure transducer, and intravesical 25 pressure' (IVP) was continuously recorded. The test compound was administered intradermally at 30 minutes before the administration of carbachol (1.8 rg/kg). Percent inhibition of IVP increase by test compound was calculated by dividing IVPa (IVP increase induced by 30 carbachol after test compound administration) by IVPb (IVP increase induced by carbachol just before test compound administration). 35 WO 2006/033446 PCT/JP2005/017669 18 Test Result Treatment Percent inhibition of IVP increase Test Compound (1) 78 (0.032 mg/kg) Preferred-embodiments of the object compound [I] are 5 as follows: R6 -X- is y , in which -Y- is bond, -0-, -NH

R

4

R

5 10 or -CH 2 -, and

R

4 , R 5 and R 6 are each independently hydrogen, lower, alkyl (more preferably Cl-C 4 alkyl) or hydroxy(lower)alkyl (more preferably hydroxy(Cl-C 4 )alkyl). 15 More preferred embodiments of the object compound [I] are as follows: R is. hydrogen, halogen (more preferably fluoro or chloro), nitro or amino, 20 R 2 is hydrogen or lower alkyl (more preferably Cl-C 4 alkyl, most preferably methyl), R3 is hydrogen, R7 is hydrogen, lower alkyl (more preferably C 1

-C

4 alkyl, most preferably isopropyl or isobutyl), 25 cyclo(lower)alkyl (more preferably cyclo(C 3

-C

6 )alkyl, most preferably cyclopentyl), -Z-R 9 .or

R

9 -N , in which -Z- is -0-, -S-, -SO- or R9 -SO2-, and 30 each R 9 is independently hydrogen, lower alkyl (more preferably Cl-C 4 alkyl, most preferably propyl, isopropyl or isobutyl) WO 2006/033446 PCT/JP2005/017669 19 or cyclo(lower)alkyl (more preferably cyclo(C 3

-C

6 )alkyl, most preferably cyclopentyl, cyclohexyl or cycloheptyl), and 5 R 8 is -D-E-R 10 , in which -D- is -CONHSO 2 - or -SO 2 NHCO-, E is bond or lower alkylene (more preferably

C

1

.-C

4 alkylene, most preferably methylene, ethylene, trimethylene, 3,3-dimethyl trimethylene or tetramethylene), and 10 RIO is halogen, cyano, carboxy, lower alkoxycarbonyl (more preferably Cl-C 4 alkoxycarbonyl, most preferably methoxycarbonyl), carbamoyl, pyridyl, 15 -O-Ril or -N , in which each R 11 is R11 independently hydrogen, lower alkyl (more preferably Cl-C 4 alkyl, most preferably methyl or ethyl), lower 20 alkanoyl (more preferably C 1

-C

4 alkanoyl, most preferably acetyl) or lower alkoxycarbonyl (more preferably Cl-C 4 alkoxycarbonyl, most preferably tert -butoxycarbonyl). 25 Furthermore preferred embodiments of the compound [I] are as follows: R6 30 -X- is y , in which -Y- is bond, -0-, -NH

R

4

R

5 or -CH 2 -, and

R

4 , R 5 and R 6 are each hydrogen, R7 is lower alkyl (more preferably Cl-C 4 alkyl, most 35 preferably isopropyl or isobutyl), cyclo(lower)alkyl WO 2006/033446 PCT/JP2005/017669 20 (more preferably cyclo(C 3

-C

6 )alkyl, most preferably cyclopentyl), -Z-R 9 or H N R in which -Z- is -0- or -S-, and 5 each R9 is independently lower alkyl or cyclo(lower)alkyl (more preferably Cl-C 4 alkyl, most preferably propyl, isopropyl or isobutyl) or cyclo(lower)alkyl (more 10 preferably cyclo(C 3

-C

6 )alkyl, most preferably cyclopentyl, cyclohexyl or cycloheptyl), and R8 is -D-E-R10, in which -D- is -CONHSO 2 -or -SO 2 NHCO-, E is bond or lower alkylene (more preferably, 15 Ci-C 4 alkylene, most preferably methylene, ethylene, trimethylene, 3,3-dimethyl trimethylene or tetramethylene), and R10 is cyano, carboxy, carbamoyl, pyridyl, 20 -O-R' 1 or -Nil , in which each R is R11 independently hydrogen lower alkyl (more preferably C 1

-C

4 alkyl, most preferably methyl or ethyl). 25 The following Preparations and Examples are given for the purpose of illustrating this invention. The group of "carbamoyl" aforementioned may be hereinafter referred to as a group of "aminocarbonyl". 30 Preparation 1 To a solution of tert-butyl [(2R)-2-hydroxy-2 phenylethyl][2-[3'-(isopropoxy)-4'-[[(methylsulfonyl) amino]carbonyl]-4-biphenylyl]ethyl]carbamate (65 mg) in 35 1,4-dioxane (2 ml) was added hydrochloric acid 1,4-dioxane WO 2006/033446 PCT/JP2005/017669 21 solution (4N, 4*ml) at room temperature and the mixture was stirred at the same temperature for 2.5 hours. The mixture was evaporated under reduced pressure to give 4' [2- [ [ (2R) -2-hydroxy-2-phenylethyl]amino]ethyl] -3 5 isopropoxy-N-(methylsulfonyl)-4-biphenylcarboxamide hydrochloride (38 mg). NMR (200 MHz, DMSO-d 6 , 8): 1.37 (6H, d, J=5.7Hz), 3.06-3.25 (6H, m), 3.38 (3H, s), 4.97-5.00 (2H, m), 6.23 (1H, br s), 7.28-7.48 (9H, 'm), 7.72 10 7.79 (3H, m) (+)ESI-MS (m/z): 497 (M+H)+ Example 1 The following compounds were obtained according to a 15 similar manner to that of Preparation 1. (1) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-N [(3-hydroxypropyl)sulfonyl]-3-isopropoxy-4-biphenyl carboxamide hydrochloride 20 NMR (200 MHz, DMSO-d 6 , 8): 1.36 (6H, d, J=6.OHz), 1.81-1.95 (2H, m), 2.99-2.73 (6H, m), 3.47-3.58 (4H, m), 4.75 (1H, t, J=5.OHz), 4.91-5.05 (2H, m), 6.24 (1H, d, J=4.0Hz), 7.31-7.43 (9H, m), 7.68-7.76 (3H, m) 25 (+)ESI-MS (m/z): 541 (M+H)+ (2) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-N [(3 -hydroxypropyl) sulfonyl] -3- (isopropylthio) -4 biphenylcarboxamide hydrochloride 30 NMR (200 MHz, DMSO-d 6 , 8): 1.25 (6H, d, J=6.5Hz), 1.85-1.99 (2H,'m), 3.02-3.27 (6H, m), 3.49-3.58 (4H, m), 3.62-3.72 (1H, m), 4.76 (1H, br s), 4.95-5.04 (1H, m), 6.23 (1H, d, J=4Hz), 7.31 7.42 (7H, m), 7.55-7.64 (2H, m), 7.70-7.74 (3H, 35 m), 8.92 (1H, br s), 9.26 (1H, br s), 12.14 (1H, WO 2006/033446 PCT/JP2005/017669 22 s) (-)ESI-MS (m/z): 555 (M-H)~ (3) 3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2 5 phenylethyl]amino]ethyl]-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.34-2.01 (12H, m), 2.99 3.27 (6H, m), 3.46-3.59 (4H, m), 4.71-4.84 (2H, m), 4.94-5.04 (1H, m), 6.23 (1H, d, J=3.5Hz), 10 7.32-7.43 (9H, m), 7.71-7.75 (3H, m) (-)ESI-MS (m/z): 579 (M-H)~ (4) 3-(Cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4' [2-[ [(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl] 15 4-biphenylcarboxamide dihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.35-2.02 (12H, m), 3.05 3.39 (6H, m), 3.48-3.60 (4H, m), 4.75-4.87 (1H, m), 5.27-5.35 (1H, m), 7.33-7.44 (4H, m), 7.71-. 7.75 (3H, m), 7.98 (1H, dd, J=5.5, 8.5Hz), 8.49 20 (1H, d, J=8.5Hz), 8.83-8.91 (2H, m), 9.30 (lH, br s),,9.41 (1H, br s), 11.18 (1H, s) (-)ESI-MS (m/z): 580 (M-H) (5) 3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2-(3 25 pyridyl)ethyl]amino]ethyl]-N-[(2-methoxyethyl) sulfonyl]-4-biphenylcarboxamide dihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.31-2.04 (10H, m), 3.04 3.50 (6H, m), 3.23 (3H, s), 3.72-3.84 (4H, m), 4.78-4.89'(1H, m), 5.27-5.37 (1H, m), 7.34-7.45 30 (4H, 'm), 7.68-7.79 (3H, m), 8.00 (1H, dd, J=5.5, 8.4Hz), 8.51 (1H, d, J=8.4Hz), 8.83-8.92 (2H, m), 9.33 (1H, br s), 9.45 (1H, br s), 11.19 (1H, s) (-)ESI-MS (m/z): 580 (M-H)~ 35 (6)' 3-(Cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]- 4 '-[2- WO 2006/033446 PCT/JP2005/017669 23 [[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4 biphenylcarboxamide dihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.30-2.01 (10H, m), 3.02 3.49 (6H, m), 3.67 (2H, t, J=6.OHz), 3.84 (2H, t, 5 J=5.8Hz), 4.75-4.89 (1H, m), 5.26-5.37 (1H, m), 7.32-7.45 (4H, m),.7.69-7.82 (3H, m), 7.97 (1H, d, J=5.4Hz), 8.5 (1H, d, J=8.OHz), 8.82-8.93 (2H, m), 9.31 (1H, br s), 9.43.(1H, br s), 11.1 (1H, br s) 10 (-)ESI-MS (m/z): 566 (M-H)~ (7) N-[(3-Hydroxypropyl)sulfonyl]-4'-[2-[[(2R)- 2 -hydroxy 2-(3-pyridyl)ethyl]aminolethyl]-3-isopropoxy- 4 biphenylcarboxamide dihydrochloride 15 NMR (200 MHz, DMSO-d 6 , 8): -1.37 (6H, d, J=6Hz), 1.81 1.96 (2H, m), 3.03-3.6 (8H, m), 4.91-5.03 (1H, m), 5.25-5.34 (1H, m), 7.32-7.44 (4H, m), 7.68 7.77 (3H, m), 7.96 (1H, dd, J=5.6, 8Hz), 8.46 (1H, d, J=8Hz), 8.8-8.89 (2H, m), 9.26 (1H, br 20 s), 9.37 (1H, br s), li.22 (1H, s) (-)ESI-MS (m/z): 540 (M-H) (8) 3-(Cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4'-[2 [[(2R)-2-hydroxy-2-phenylethyl]amifno]ethyl]-4 25 biphenylcarboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.31-2.03 (10H, m), 3.00 3.29 (6H, m), 3.66 (2H, t, J=6Hz), 3.79-3.87 (2H, m), 4.76-4.87 (1H, m), 4.95-5.11 (2H, m), 6.23 (1H, d, J=3.6Hz), 7.31-7.44 (9H, m), 7.69-7.81 30 (3H, m) (-)ESI-MS (m/z): 565 (M-H)~ Preparation 2 The following compounds were obtained according to a 35 similar manner to that of Example 2.

WO 2006/033446 PCT/JP2005/017669 24 (1) Methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2 (3-pyridyl)ethyl]amino]ethyl]-3-(cycloheptyloxy)-4 biphenylcarboxylate 5 (+)ESI-MS (m/z): 589 (M+H)+ (2) Methyl 4'-[3-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2 (3-pyridyl)ethyl]amino]propyl]-3-isopropoxy-4 biphenylcarboxylate 10 (+)ESI-MS (m/z): 549 (M+H)+, 571 (M+Na)+ Preparation 3 To a solution of methyl 4'-[2-[(tert-butoxycarbonyl) [(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3 15 (cycloheptyloxy)-4-biphenylcarboxylate (813 mg) in methanol (8.1 ml) and tetrahydrofuran (2.4 ml) was added IN sodium hydroxide (4.14 ml) and the mixture was stirred at room temperature for 24 hours. The mixture was quenched by the addition of iN hydrochloric acid (4.14 ml) 20 and the solvent was removed by evaporation. The residue was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give 4'-[2-[(tert-butoxycarbonyl)[(2R)-2 hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-(cycloheptyl oxy)-4-biphenylcarboxylic acid (575 mg) as a white solid. 25 (-)ESI-MS (m/z): 573 (M-H)~ Preparation 4 To a solution of 4-bromo-2-cyclopentylbenzoic acid (4.05 g) in N,N-dimethylformamide (40 ml) was added N,N' 30 carbonyldiimidazole (2.68 g) at room temperature and the mixture was stirred for 4 hours. To the mixture were added 3-(aminosulfonyl)propyl acetate (3.0 g) and 1,8 diazabicyclo[5.4.0]undec-7-ene (2.7 ml) and the whole was stirred at 120 0 C for 20 hours. After cooling to room 35 temperature, the mixture was quenched by the addition of WO 2006/033446 PCT/JP2005/017669 25 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (100 ml, 50 ml). The combined extracts were washed with water (100 ml x 2) and brine (100 ml), and dried over magnesium sulfate. Filtration followed by 5 evaporation gave a yellow solid (6.77 g) which was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give 3-[[(4-bromo-2-cyclopentylbenzoyl) amino]sulfonyl]propyl acetate (5.20 g) as a white solid. (-)ESI-MS (m/z): 430, 432 (M-H)~ 10 Preparation 5 A mixture of 3-[[(4-bromo-2-cyclopentylbenzoyl) amino]sulfonyl]propyl acetate (5.17.g), bis(pinacolato) diboron (3.34 g), [1,1'-bis(diphenylphosphino)ferrocene] 15 dichloropalladium(II), complex with dichloromethane (1:1, 977 mg), 1,1'-bis(diphenylphosphino)ferrocene (331 mg), potassium acetate (4.70 g) and 1,4-dioxane (52 ml) was stirred at 95 0 C for 2 hours. After cooling to room temperature, the mixture was quenched by the addition of 20 0.5N hydrochloric acid (100 ml) and extracted with ethyl acetate (100 ml). The organic layer was separated and washed with water (100 ml) and 10% sodium chloride solution (100 ml). To the organic layer were added water (100 ml), ammonium acetate (4.15 g) and sodium periodate 25 (8.95 g). The mixture was stirred at room temperature overnight. The insoluble solid was filtered off and washed with ethyl acetate, and the organic layer was separated. The organic layer was washed with 0.5N hydrochloric acid -(100 ml) and brine (100 ml), and dried 30 over magnesium sulfate. Filtration followed by evaporation gave a brown solid (6.62 g) which was chromatographed on silica gel (eluent: ethyl acetate/methanol) to give [4-[[[[3-(acetyloxy)propyl] sulfonyl]amino]carbonyl]-3-cyclopentylphenyl]boronic acid 35 ~(3.34 g) as a brown solid.

WO 2006/033446 PCT/JP2005/017669 26 (-)ESI-MS (m/z): 396 (M-H) Preparation 6 [4-[[[[3-(Acetyloxy)propyl]sulfonyl]amino]carbonyl] .5 3-cyclopentylphenyl]boronic acid (3.28 g) was dissolved in 2.5N hydrogen chloride in methanol (20 ml) and the mixture was stirred at room temperature for 17 hours. The solvent was removed by evaporation to give [3-cyclopentyl-4-[[[( 3 hydroxypropyl)sulfonyl]amino]carbonyl]phenyl]boronic acid 10 (3.16 g) as a brown solid. (-)ESI-MS (m/z): 354 (M-H)~ Preparation. 7 A mixture of 2-bromoethanol (7.0 g) and potassium 15 thiocyanate (5.4 g) in methanol (40 ml) was refluxed for 7 hours. After precipitate was filtered off, thefiltrate was evaporated under reduced pressure. The residue was suspended in chloroform/methanol (5/1). The precipitate was filtered off. The filtrate was evaporated under 20 reduced pressure to, give the thiocyanate (4.4 g). To a mixture of the thiocyanate in pyridine (4.8 ml)/dichloromethane (20 ml) was added acetic anhydride (5.3 ml) in dichloromethane (5 ml) at 5 0 C. The mixture was stirred at room temperature for 6 hours. The 25 precipitate was filtered off. The filtrate was washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 2-thiocyanatoethyl acetate (5.6 g). NMR (200 MHz, DMSO-d 6 , 8): 2.06 (3H, s), 3.36 (2H, t, 30 J=5.8Hz), 4.32 (2H, t, J=5.8Hz) Preparation 8 A solution of 2-thiocyanatoethyl acetate (5.6 g) in water (20 ml) was bubbled with chlorine gas for 20 minutes 35 under ice-cooling with stirring followed by extraction WO 2006/033446 PCT/JP2005/017669 27 with dichloromethane. After the extract was dried over sodium sulfate, the solvent was evaporated under reduced pressure to give sulfonyl chloride (6.0 g, colorless oil). The sulfonyl chloride was dissolved in dichloromethane 5 (60 ml) and bubbled with ammonia gas for 1 hour under ice cooling. The precipitate was filtered off, and the filtrate was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel 10 (chloroform/methanol=92/8 to 90/10) to give 2 (aminosulfonyl)ethyl acetate (385 mg). NMR (200 MHz, CDCl 3 , &): 2.11 (3H, s), 3.47 (2H, t, J=6.OHz), 4.54 (2H, t, J=6.0Hz), 5.10 (2H, br s) (-)ESI-MS (m/z): 166 (M-H) 15 Preparation 9 A mixture of [(2-bromoethoxy)methyl]benzene (6.0 g) and sodium sulfate (3.9 g) in water (12 ml) and ethanol (36 ml) was refluxed overnight. The mixture was acidified 20 with conc. hydrochloric acid under ice-cooling. The mixture was evaporated under reduced pressure. The residue was suspended in dichloromethane/methanol (4/1) and filtered off through Celite pad. The filtrate was evaporated to give 2-(benzyloxy)ethanesulfonic acid (4.5 25 g). (-)ESI-MS (m/z): 215 (M-H) Preparation 10 To a 2-(benzyloxy)ethanesulfonic acid (4.0 g) was 30 added thionyl chloride (13.5 ml) dropwise at ambient temperature for 15 minutes and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added dropwise N,N-dimethylformamide (0.072 ml) at ambient temperature. The mixture was stirred at the same 35 temperature for 20 minutes and refluxed for 1 hour. After WO 2006/033446 PCT/JP2005/017669 28 cooling down to room temperature, the mixture was evaporated under reduced pressure to give 2-(benzyloxy) ethanesulfonyl chloride (4.1 g). NMR (200 MHz, CDCl 3 , 8): 3.92-4.08 (4H, m), 4.60 (2H, 5 s), 7.32-7.39 (5H, m) Preparation 11 To a 28% ammonium hydroxide (10 ml) was added dropwise 2-(benzyloxy)ethanesulfonyl chloride '(4.1 g) in 10 dichloromethane (10 ml) over 10 minutes under ice-cooling. The mixture was stirred at ambient temperature overnight. The organic layer was separated and the aqueous layer was extracted with dichloromethane/methanol (5/1). The combined organic layer was dried over sodium sulfate and 15 evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=50/50) to give 2-(benzyloxy) ethanesulfonamide (1.6 g). NMR (200 MHz, CDCl 3 , 5): 3.39 (2H, t, J=5.5Hz), 3.96 20 (2H, t, J=5.5Hz), 4.57 (2H, s), 4.84 (2H, br s), 7.30-7.42 (5H, m) (+)ESI-MS (m/z): 238 (M+Na)+ Preparation 12 25 The following compounds were obtained according to a similar manner to that of Preparation 4. (1) 3-[[[4-Bromo-2-(cyclohexyloxy)benzoyl].amino] sulfonyl]propyl acetate 30 (-)ESI-MS (m/z): 460 (M-H) (2) N-[[2-(Benzyloxy)ethyl]sulfonyl]- 4 -bromo-2 (cyclohexyloxy)benzamide (-)ESI-MS (m/z): 494 (M-H)~ 35 WO 2006/033446 PCT/JP2005/017669 29 (3) 3-[[(4-Bromo-2-isopropoxybenzoyl)amino]sulfonyl] propyl acetate (+)ESI-MS (m/z): 444 (M+Na)+ 5 Preparation 13 The following compounds were obtained according to a similar manner to that of Preparation 5. (1) [4-[[[[3-(Acetyloxy)propyl]sulfonyl]amino]carbonyl] 10 3-(cyclohexyloxy)phenyl]boronic acid (+)ESI-MS (m/z): 450 (M+Na)+ (2) [4-[[[[2-(Benzyloxy)ethyl]sulfonyl]amino]carbonyl]- 3 (cyclohexyloxy)phenyl boronic acid 15 (+)ESI-MS (m/z): 484 (M+Na)+ (3) [4- [[[[3- (Acetyloxy)propyl]sulfonyl]amino]carbonyl] 3-isopropoxyphenyl]boronic acid (+)ESI-MS (m/z): 410 (M+Na)+ 20 (4) [4-[[[[3-(Acetyloxy)propyl]sulfonyl]amino]carbonyl] 3-isobutylphenyl]boronic acid (-)ESI-MS (m/z): 384 (M-H)~ 25 Preparation 14 The following compounds were obtained according to a similar manner to that of Preparation 6. (1) [3- (Cyclohexyloxy) -4- [ [ [(3-hydroxypropyl)sulfonyl] 30 amino]carbonyliphenyl]boronic acid (+)ESI-MS (m/z): 450 (M+Na)+ (2) [4-[[[(3-Hydroxypropyl)sulfonyl]amino]carbonyl]-3 isopropoxyphenyl]boronic acid 35 (+)ESI-MS (m/z): 368 (M+Na)+ WO 2006/033446 PCT/JP2005/017669 30 (3) [4-[[[(3-HydroxyprOpYl)sulfonyl]amino]carbonyl]-3 isobutylphenyl]boronic acid (-)ESI-MS (m/z): 342 (M-H)~ 5 Preparation 15 The following compounds were obtained according to a similar manner to that of Example 15. 10 (1) Methyl 4'-[2-[(tert-butoxycarbonyl)[(lS, 2 R)-2 hydroxy-1-methyl-2-phenylethyllamino]ethyl]-3 (cyclohexyloxy) -4 -biphenylcarboxylate (+)ESI-MS (m/z): 610 (M+Na)+ 15 (2) Methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-phenyl-2 (tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3 cyclopentyl-4-biphenylcarboxylate (+)ESI-MS (m/z): 650 (M+Na)+ 20 (3) tert-Butyl [2-[4'-(aminosulfonyl)-3'-(cyclohexyloxy) 4-biphenylyllethyl][(2R)-2-phenyl-2-(tetrahydro-2H pyran-2-yloxy)ethyl]carbamate (+)ESI-MS (m/z): 701 (M+Na)+ 25 Preparation 16 The following compounds were obtained according to a similar manner to that of Preparation 3. (1) 4'-[2-[(tert-Butoxycarbonyl)[(1S,2R)-2-hydroxy-l 30 methyl-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy) 4-biphenylcarboxylic acid (+)ESI-MS (m/z): 610 (M+Na)+ (2) 4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-phenyl-2 35 (tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3- WO 2006/033446 PCT/JP2005/017669 31 cyclopentyl-4-biphenylcarboxylic acid (-)ESI-MS (m/z): 612 (M-H) (3) 4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-(3-chlorophenyl) 5 2-hydroxyethyl]amino]ethyl]-3-(isopropylthio)-4 biphenylcarboxylic acid (-)ESI-MS (m/z): 568, 570 (M-H)~ (4) 4'-[3-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2-(3 10 pyridyl)ethyl]aminoipropyl]-3-isopropoxy-4 biphenylcarboxylic acid (-)ESI-MS (m/z): 533 (M-H)~ Preparation 17 15 The following compound was obtained according to a similar manner to that of Example 26. Methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3 20 (isopropylthio) -4-biphenylcarboxylate (+)ESI-MS (m/z): 606 (M+Na)+ Preparation 18 The following compound was obtained according to a 25 similar manner to that of Example 11. 3-[[(4-Bromo-2-isobutylbenzoyl)amino]sulfonyl]propyl acetate (-)ESI-MS (m/z): 418, 420 (M-H)~ 30 Preparation 19 The following compounds were obtained according to a similar manner to that of Preparation 7. 35 (1) Methyl 3-thiocyanatopropanoate WO 2006/033446 PCT/JP2005/017669 32 (+)ESI-MS (m/z): 168 (M+Na)+ (2) 4-Hydroxybutyl thiocyanate NMR (200 MHz, CDCl 3 , 8): 1.69-1.79 (2H, m), 1.9-2.03 5 (2H, m), 2.99-3.06 (2H, m), 3.68-3.74 (2H, m), 4.00 (1H, s) (3) 4-Thiocyanatobutyl acetate NMR (200 MHz, CDCl 3 , 8): 1.77-2.07 (4H, m), 2.10 (3H, 10 s), 2.99 (2H, t, J=7Hz), 4.12 (2H, t, J=6.lHz) Preparation'20 Methyl 3-thiocyanatopropanate (2.00 g) was dissolved in water (20 ml) and cooled at 0 0 C. Chlorine gas was 15 bubbled into the solution for 1 hour at the same temperature. The reaction mixture was poured into the mixture of cold water and diethyl ether and the aqueous layer was separated. The organic layer was washed with brine and dried over magnesium sulfate. Evaporation of 20 the solvent afforded methyl 3-(chlorosulfonyl)propanoate (2.31 g). NMR (200 MHz, CDCl 3 , 8): 3.06 (2H, t, J=8Hz), 3.79 (3H, s), 4.01 (2H, d, J=8Hz) 25 Preparation 21 Methyl 3-(chlorosulfonyl)propanoate (2.31 g) was dissolved in dichloromethane (1.85 ml) and tetrahydrofuran (4.60 ml) and cooled at -10 0 C. Ammonia gas was bubbled into the solution for 1.5 hours at the same temperature. 30 After filtration through Celite, the reaction mixture was evaporated. The residue was purified by column chromatography on silica gel eluting with chloroform and methanol to give methyl 3-(aminosulfonyl)propanoate (1.80 'g). 35 NMR (400 MHz, CDCl 3 , 6): 2.90 (2H, t, J=7.2Hz), 3.48 WO 2006/033446 PCT/JP2005/017669 33 (2H, t, J=7.2Hz), 3.74 (3H, s), 4.94 (2H, br s) (+)ESI-MS (m/z): 190 (M+Na)+ Preparation 22 5 The following compound was obtained according to a similar manner to that of Preparation 20. 4-(Chlorosulfonyl)butyl acetate NMR (200 MHz, CDCl 3 , 6): 1.79-1.93 (2H, in), 2.07 (3H, 10 s), 2.07-2.23 (2H, m), 3.'72 (2H, t, J=7.7Hz), 4.14 (2H, t, J=6.1Hz) Preparation 23 The following compound was obtained according to a 15 similar manner to that of Preparation 21. 4-(Aminosulfonyl)butyl acetate (-)ESI-MS (m/z): 194 (M-H)~ 20 Preparation 24 To an ammonium hydroxide (28%, 80 ml) was added a solution of 4-bromo-2-fluorobenzenesulfonyl chloride (10 g) in dichloromethane (80 ml) dropwise for 1 hour at approximately 0 0 C. The reaction mixture was stirred 25 vigorously for an additional 2 hours at the same temperature. The phases were separated. The aqueous phase was washed with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 4-bromo-2-fluorobenzenesulfonamide 30 (8.0 g). (+)ESI-MS (m/z): 276 (M+Na)+ Preparation 25 To a suspension of sodium hydride (60%, 0.65 g) in 35 N,N-dimethylformamide (22 ml) was added a solution of WO 2006/033446 PCT/JP2005/017669 34 cyclohexanol (2.7 ml) in N,N-dimethylformamide (6 ml) for 30 minutes at ambient temperature. The suspension was stirred for 30 minutes at room temperature. A solution of 4-bromo-2-fluorobenzenesulfonamide (3 g) in N,N 5 dimethylformamide (13 ml) was added dropwise over 30 minutes at ambient temperature. The suspension was stirred at room temperature for 1 hour and at 60'C for 2 hours. The suspension was poured into a mixture of ice (35 ml) and aqueous hydrochloric acid solution (1N, 35 -ml), 10 and the mixture was stirred at room temperature for 1 hour. The mixture was filtered to collect precipitate and the precipitate was washed with water and hexane. The precipitate was dried under reduced pressure to give 4 bromo-2-(cyclohexloxy)benzenesulfonamide (3.6 g). 15 (+)ESI-MS (m/z): 356 (M+Na)+ Preparation 26 To a solution of 4-bromo-2-(cyclohexyloxy) benzenesulfonamide (3.6 g) in 1,4-dioxane (35 ml) were 20 added bis(pinacolate)diboron (3.0 g), dichlorobis (triphenylphosphine)palladium(If) (528 mg) and potassium acetate (3.16 g), and the mixture was stirred at 95 0 C for 2 hours under nitrogen atmosphere. After cooling down to room temperature, the mixture was poured into brine and 25 extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give residue (6.4 g). To a mixture of the above residue in ethyl acetate (50 ml) and water (50 ml) were added ammonium acetate (1.8 30 g) and sodium periodate (5.0 g). The mixture was stirred at room temperature overnight. Precipitate was filtered off and the precipitate was washed with ethyl acetate/methanol (9/1). The filtrate was washed with aqueous hydrochloric acid solution (0.5N) and brine, dried 35 over sodium sulfate and evaporated under reduced pressure.

WO 2006/033446 PCT/JP2005/017669 35 The residue was purified by. column chromatography on silica gel (chloroform/methanol=95/5) to give [4-(amino sulfonyl)-3-(cyclohexyloxy)phenylboronic acid (2.5 g). (+)ESI-MS (m/z): 322 (M+Na)+ 5 Example 2 A mixture. of tert-butyl [2-(4-bromophenyl)ethyl] [(2R)-2-(3-chlorophenyl)-2-h ydroxyethyl]carbamate (250 mg), [4- [ [ [(3-hydroxypropyl)sulfonyl]amino]carbonyl.] -3 10 isopropoxyphenyl]boronic acid (228 mg), [1,1' bis (diphenylphosphino) ferrocene] dichloropalladium( II), complex with dichloromethane (1:1, 67.3 mg), 1,1' bis(diphenylphosphino)ferrocene (45.7 mg), N,N dimethylformamide (5 ml) and 2N sodium carbonate solution 15 (1.32 ml) was stirred at 80'C for 2 hours. After cooling to room temperature, the mixture was quenched by the addition of 1N hydrochloric acid (2.64 ml) and partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, washed with water (20 ml x 2) 20 and brine (20 ml), and dried over magnesium sulfate. Filtration followed by evaporation gave a brown foam which was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give tert-butyl [(2R)-2-'(3-chlorophenyl)-2 hydroxyethyl] [2- [4' - [[[(3 -hydroxypropyl) sulfonyl] amino ] 25 carbonyl]-3'-isopropxy-4-biphenylyl]ethyl]carbamate (236 mg) as a pale yellow solid. (-)ESI-MS (m/z): 673 (M-H)~ Example 3 30 To a solution of tert-butyl [(2R)-2-(3-chlorophenyl) 2 -hydroxyethyl] [2- [4' - [[[(3 -hydroxypropyl) sulfonyl] amino] carbonyl]-3'-isopropoxy-4-biphenylyl]ethyl]carbamate (231 mg) in 1,4-dioxane (2.3 ml) was added 4N hydrogen chloride in 1,4-dioxane (2.3 ml) and the mixture was stirred at 35 room temperature for 5 hours. The precipitates were WO 2006/033446 PCT/JP2005/017669 36 collected by filtration, washed with 1,4-dioxane, and dried under reduced pressure to give 4'-[2-[[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-N-[(3-hydroxy propyl)sulfonyl]-3-isopropoxy-4-biphenylcarboxamide 5 hydrochloride (158 mg) as a white solid. NMR (400 MHz, DMSO-d 6 , 8): 1.33 (6H, d, J=6.2Hz), 1.85-1.92 (2H, m), 3.01-3.12 (3H, m), 3.19-3.27 (3H, m), 3.49-3.55 (4H, m), 4.74 (1H, t, J=5.lHz), 4.92-5.04 (2H, m), 6.37 (1H, d, 10 J=4.OHz), 7.34-7.49 (8H, m), 7.70 (1H, d, J=8.lHz),! 7.74 (2H, d, J=8.4Hz), 9.06 (2H, br), 11.2 (1H, br) (-)ESI-MS (m/z): 573 (M-H)~ 15 Example 4 The following compounds were obtained according to a similar manner to that of Example 2. (1) tert-Butyl [(2R)-2-hydroxy-2-phenylethyl][ 2

-[[

4

'

20 [[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3' isopropoxy-4-biphenylyl]oxy]ethyl]carbamate (-)ESI-MS (m/z): 655 (M-H)~ (2) tert-Butyl [2-[[3'-(cyclohexyloxy)-4'-[[[(3-hydroxy 25 propyl)sulfonyl]amino]carbonyl]-4-biphenylyl]oxy] ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (-)ESI-MS (m/z): 695 (M-H)~ (3) tert-Butyl [2-[[3',cyclopentyl-4'-[[[(3-hydroxy 30 propyl)sulfonyl]amino]carbonyl]-4-biphenylylloxy] ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (-)ESI-MS (m/z): 665 (M-H)~ (4) tert-Butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] 35 [2-[[4'-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]- WO 2006/033446 PCT/JP2005/017669 37 3'-isopropoxy-4-biphenylyl]oxy]ethyl]carbamate (-)ESI-MS (m/z): 689 (M-H.)~ (5) tert-Butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl] 5 [2-[ [3'-cyclopentyl-4'-[[[(3-hydroxypropyl)sulfonyl] amino]carbonyl]-4-biphenylyl]oxy]ethyl]carbamate (-)ESI-MS (m/z): 699 (M-H)~ (6) 3 -[[[[4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-(6-chloro 10 3-pyridyl)-2-hydroxyethyl]amino]ethoxy]-3 (cyclohexyloxy)-4-biphenylyl]carbonyl]amino] sulfonyl propyl acetate (-)ESI-MS (m/z): 772 '(M-H)~ 15 (7) tert-Butyl [2-[3'-(cyclohexyloxy)-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl] [(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl]carbamate (-)ESI-MS (m/z): 724 (M-H)~ 20 (8) tert-Butyl [(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl][2 [4'-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3' isobutyl-4-biphenylyl]ethyl]carbamate (-)ESI-MS (m/z): 682 (M-H)~ 25 (9) tert-Butyl [2-[3'-cyclopentyl-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl] [(2R)-2-hydroxy-2-(4-nitorophenyl)ethyl carbamate (-)ESI-MS (m/z): 694 (M-H)~ 30 (10) tert-Butyl [2-[4'-[[[[2-(benzyloxy)ethyl]sulfonyl] amino]carbonyl]-3'-(cyclohexyloxy)-4-biphenylyl] ethyl][(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl] carbamate 35 (11) tert-Butyl [2-[[3'-(cyclohexyloxy)-4'-[[[(3-hydroxy- WO 2006/033446 PCT/JP2005/017669 38 propyl)'sulfonyl]amino]carbonyl]-4-biphenylyl]oxy] ethyl] [(2R) -2-hydroxy-2- (4-nitrophenyl)ethyl] carbamate (-)ESI-MS (m/z): 740 (M-H)~ 5 (12) tert-Butyl [2-[[3'-cyclopentyl-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl]oxy] ethyl][(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl] carbamate 10 (-)ESI-MS (m/z): 710 (M-H) (13) tert-Butyl [2-[3'-(cyclohexyloxy)-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl) [(2R) -2-hydroxy-2- (3-nitrophenyl)ethyl]carbamate 15 (-)ESI-MS (m/z): 724 (M-H)~ (14) 4 '-[2-[[(1S,2R)-2-Hydroxy--methyl-2-phenylethyl] amino] ethyl] -N- [(3 -hydroxypropyl) sulfonyl] -3 isopropoxy-4-biphenylcarboxamide hydrochloride 20 NMR (200 MHz, DMSO-d 6 , 8): 0.97 (3H, t, J=6.6lz), 1.26 (6H, d, J=6.OHz), 1.7-2.0 (2H, m), 3.0-3.2 (2H, m), 3.3-3.7 (6H, m), 4.74 (1H, m), 4.97 (1H, m), 5.20 (1H, m), 6.13 (1H, m), '7.1-7.5 (9H, m), 7.6-7.9 (3H, m) 25 ESI-MS (m/z): 555 (M+H) (15) N-[(3-Hydroxypropyl)sulfonyl]-4'-[2-[[(2R)-2-hydroxy 2-(3-pyridyl)ethyl]amino]ethyl]-3-propoxy-4-biphenyl carboxamide dihydrochloride 30 NMR (200 MHz, DMSO-d 6 , 8): 1.01 (3H, t, J=6.2Hz), 1.7-2.0 (4H, m), 2.8-4.2 (12H, m), 5.24 (1H, m), 7.1-7.4 (4H, m), 7.5-8.0 (4H, m), 8.36 (1H, m), 8.7-9.0 (2H, m) ESI-MS (m/z): 542 (M+H) .35 WO 2006/033446 PCT/JP2005/017669 39 (16) [3-[3'-(Cyclohexyloxy)-4'-[[[(3-hydroxypropyl) sulfonyl]amino]carbonyl]-4-biphenylyl propyl][(2R)-2 hydroxy-2-phenylethyl]carbamate (-)ESI-MS (m/z): 693. (M-H) 5 (17) tert-Butyl [(2R)-2-hydroxy-2-phenylethyl][3-[ 4

'

[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3' isopropoxy-4-biphenylyl propyl]carbamate (-)ESI-MS (m/z): 653 (M-H)~ 10 (18) tert-Butyl [(2R)-2-hydroxy-2-phenylethyl] [3-[4' [[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3' isobutyl-4-biphenylyl]propyl]carbamate (-)ESI-MS (m/z): 651 (M-H)~ 15 (19) tert-Butyl [3-[3'-cyclopentyl-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl]propyl] [(2R)-2-hydroxy-2-phenylethyl]carbamate (-)ESI-MS (m/z): 663 (M-H)~ 20 (20) tert-Butyl [3-[3'-(cyclohexyloxy),-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl] propyl][(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl] carbamate 25 (-)ESI-MS (m/z): 738 (M-H)~ (21) tert-Butyl [3-[3'-cyclopentyl-4'-[[[(3-hydroxy propyl)sulfonyllamino]carbonyl]-4-biphenylyl]propyl] [(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl]carbamate 30 (-)ESI-MS (m/z): 708 (M-H)~ (22) tert-Butyl [(2R)-2-(3-chlorophenyl)-2-hydroxy ethyl][3-[4'-[[[(3-hydroxypropyl)sulfonyl]amino] carbonyl ]-3' - isopropoxy- 4 -biphenylyl ] propyl] carbamate 35 (-)ESI-MS (m/z): 687, 688, 689 (M-H) WO 2006/033446 PCT/JP2005/017669 40 (23) tert-Butyl [3-[3'-(cyclphexyloxy)-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl] propyl][(2R) -2-hydroxy-2-(3-pyridyl)ethyl]carbamate 5 (-)ESI-MS (m/z): 694-(M-H)~ Example 5 The following compounds were obtained according to a similar manner to that of Example 3. 10 (1) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethoxy]-N [(3-hydroxypropyl)sulfonyl]-3-isopropoxy-4-biphenyl carboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.37 (6H, d, J=5.9Hz), 15 1.85-1.92 (2H, m), 3.10 (1H, dd, J=10.6, 12.4Hz), 3.27 (1H, dd, J=1.8, 12.4Hz), 3.44-3.57 (6H, m), 4.35-4.44 (2H, m), 4.75 (1H, t, J=5.lHz), 4.94 5.06 (2H, m), 6.23 (1H, d, J=3.7Hz), 7.12 (2H, d, J=8.8Hz),'7.31-7.44 (7H, m), 7.71 (1H, d, 20 J=8.lHz), 7.75 (2H, d, J=8.8Hz), 9.21 (2H, br), 11.0 (1H, br) (-)ESI-MS (m/z): 555 (M-H)~ (2) 3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2-phenyl 25 -ethyl]amino]ethoxy] -N- [ (3-hydroxypropyl) sulfonyl] -4 biphenylcarboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.30-1.63 (6H, m), 1.69 1.77 (2H, m), 1.84-1.91 (2H, m), 1.93-2.01 (2H, m), 3.10 (1H, dd, J=10.6, 12.4Hz), 3.27 (1H, dd, 30 J=2.2, 12.4Hz), 3.44-3.58 (6H, m), 4.35-4.43 (2H, m), 4.74 (1H, t, J=5.lHz), 4.79-4.85 (1H, m), 5.01-5.05 (1H, m), 6.22 (1H, d, J=3.7Hz), 7.12 (2H, d, J=8.8Hz), 7.31-7.43 (7H, m), 7.74 (1H, d, J=8.lHz), 7.75 (1H, d, J=8.8Hz), 9.20 (2H, br), 35 11.0 (1H, br) WO 2006/033446 PCT/JP2005/017669 41 (-)ESI-MS (m/z): 595 (M-'H)~ (3) 3 -dyclopentyl-4'-[2-[[(2R)-2-hydroxy-2-phenylethyl] amino]ethoxy]-N-[(3-hydroxypropyl)sulfonyl]-4 5 biphenylcarboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.60-1.71 (4H, m), 1.77 1.91 (4H, m), 1.99-2.07 (2H, m), 3.08-3.13 (1H, m), 3.25-3.31,(2H, m), 3.44-3.47 (2H, m), 3.51 3.57 (4H, m), 4.34-4.42 (2H, m), 4.78 (1H, br), 10 5.01-5.05 (1H, m'), 6.23 (1H, d, J=3.7Hz), 7.11 (2H, d, J=8.8Hz), 7.31-7.46 (6H, m), 7.53 (1H, dd, J=1.5, 8.1Hz), 7.,62 (1H, d, J=1.5Hz), 7.70 (2H, d, J=8.8Hz), 9.06 (1H, br), 9.21 (1H, br), 12.1 (1H, br) 15 (-)ESI-MS (m/z): 565 (M-H)~ (4) 4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethoxy]-N-[(3-hydroxypropyl)sulfonyl]-3 isopropoxy-4-biphenylcarboxamide hydrochloride 20 NMR (400 MHz, DMSO-d 6 , 8): 1.37 (6H, d, J=6.2Hz), 1.84-1.92 (2H, m), 3'.12 (1H, dd, J=10.3, 12.4Hz), 3.28-3.31 (1H, m), 3.44 (2H, t, J=5.lHz), 3.49 3.57 (4H, m), 4.34-4.42 (2H, m), 4.74 (1H, t, J=5.1HZ), 4.94-5.07 (2H, m), 6.36 (1H, d, 25 J=4.OHz), 7.12 (2H, d, J=8.8Hz), 7.33-7.49 (6H, m), 7.71 (1H, d, J=8.lHz), 7.76 (2H, d, J=8.8Hz), 9.12 (2H, br), 11.1 (1H, br) (-)ESI-MS (m/z): 589 (M-H)~ 30 (5) 4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethoxy]-3-cyclopentyl-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.60-1.70 (4H, m), 1.77 1.91 (4H, m), 1.99-2.06 (2H, m), 3.12 (1H, dd, 35 J=10.6, 12.4Hz), 3.27-3.31 (1H, m), 3.44 (2H, t, WO 2006/033446 PCT/JP2005/017669 42 J=4.8Hz), 3.51-3.57 (4H, m), 4.32-4.41 (2H,.m), 4.76 (1H, t, J=4.8Hz), 5.02-5.06 (1H, m), 6.35 (1H, d, J=4.OHz), 7.10 (2H, d, J=8.8Hz), ,7.37 7.54 (6H, m), 7.62 (1H, d, J=1.5Hz), 7.70 (2H,.d, 5 J=8.8Hz), 9.04 (2H, br), 12.1 (1H, br) (-)ESI-MS (m/z): 599 (M-H) (6) 3-(Cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4' [2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethoxy] 10 4-biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.31-1.63 (6H, m), 1.69 1.78 (2H, m), 1.84-1.91 (2H, m), 1.93-2.00 (2H, m), 3.23-3.58 (8H,. m), 4.36-4.44 (2H, m), 4.79 4.85 (1H, m), 5.27 (1H, dd, J=2.9, 9.5Hz), 6.68 15 (1H, br), 7.12 (2H, d, J=8.8Hz), 7.34 (1H, dd, J=1.5, 8.1Hz), 7.40 (1H, d, J=1.5Hz), 7.74 (1H, d, J=8.lHz), 7.75, (2H, d, J=8.8Hz), 7.86 (1H, dd, J=5.5, 8.1Hz), 8.34 (1H, d, J=8.1Hz), 8.78 (1H, dd, J=1.5, 5.5Hz), 8.84 (1H, d, J=1.5Hz), 9.23 20 (1H, br) (-)ESI-MS (m/z): 596 (M-H) (7) 4'-[2-[[(2R)-2-(4-Aminophenyl)-2-hydroxyethyllamino] ethyl] 3-(cyclohexyloxy)-N-[(3-hydroxypropyl) 25 sulfonyl]-4-biphenylcarboxamide dihydrodhloride NMR (400 MHz, DMSO-d 6 , 8): 1.30-1.63 (6H, m), 1.71 1.76 (2H, m), 1.84-1.98 (4H, m), 3.00-3.12 (3H, m), 3.16-3.26 (3H, m), 4.49-3.58 (4H, m), 3.73 (1H, s), 4.78-4.82 (1H, m), 4.97-4.99 (1H, m), 30 6.25 (1H, s), 7.22-7.24 (2H, m), 7.34-7.43 (6H, m), 7.72-7..74 (3H, m), 8.89 (1H, br s), 9.20 (1H, br s), 9,.57 (3H, br), 11.2 (1H, br s) (-)ESI-MS (m/z): 594 (M-H)~ 35 (8) 4'-[2-[[(2R)-2-(4-Aminophenyl)-2-hydroxyethllamino]- WO 2006/033446 PCT/JP2005/017669 43 ethyll-N-[(3-hydroxypropyl)sulfonyl]-3-isobutyl- 4 biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 0.87 (6H, d, J=6.6Hz), 1.79-1.91 (3H, m), 2.73 (1H, d, J=7.OHz), 3.00 5 3.12 (3H, m), 3.16-3.26 (3H, m), 3.51-3.57 (4H, m), 4.94 (1H, dd, J=2.2, 9.9Hz), 6.25 (1H, br), 7.22 (2H, d, J=8.1Hz), 7.38 (2H, d, J=8.lHz), 7.42 (2H, d, J=8.lHz), 7.53-7.61 (3H, m), 7.70 (2H, d, J=8.lHz), 8.88 (1H, br), 9.17 (1H, br), 10 9.48 (3H, br), 12.1 (1H, br) (-)ESI-MS (m/z): 552 (M-H)~ (9) 4

'-[

2 -[[(2R)-2-(4-Aminophenyl)-2hydroxyethyl]amino] ethyl]-3-cyclopentyl-N-[(3-hydroxypropyl)sulfonyl]-4 15 biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.60-1.71 (4H, m); 1.76 1.91 (4H,-m), 1.98-2.07 (2H, m), 3.0-3.34 (7H, m), 3.51-3.58 (4H, m), 4.96-4.99 (1H, m), 6.25. (1H, br), 7.22 (2H, d, J=8.1Hz), 7.37-7.48 (5H, 20 m),-7.56 (1H, dd, J=1.5, 8.1Hz), 7.64 (1H, d, J=1.5H-z), 7.69 (2H, d, J=8.4Hz), 8.89 (1H, br), 9.18 (1H, br), 9.51 (3H, br), 12.2 (1H, br) (-)ESI-MS (m/z): 564 (M-H)~ 25 (10) 4'-[2-[[(2R)-2-(4-Aminophenyl)-2-hydroxyethyl]amino] ethyl]-3-(cyclohexyloxy)-N-[(2-hydroxyethyl) sulfonyl)-4-biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.31-1.63 (6H, m), 1.69 1.78 (2H, m), 1.92-2.01 (2H, m),3.00-3.27 (6H, 30 m), 3.65-3.85 (4H, m), 6.27 (1H, br), 7.29 (2H, d, J=8.4Hz), 7.36 (1H, dd; J=1.5, 8.1Hz), 7.39 (2H, d, J=8.4Hz), 7.42 (1H, d, J=1.5Hz.), 7.45 (2H, d, J=8.4Hz), 7.73 (2H, d, J=8.4Hz), 7.78 (1H, d, J=8.lHz), 8.95 (1H, br), 9.31 (1H, br), 35 9.86 (3H, br), 11.1 (1H, br) WO 2006/033446 PCT/JP2005/017669 44 (-)ESI-MS (m/z): 580 (M-H)~ (11) 4'-[2-[[(2R)-2-(4-Aminophenyl)-2-hydroxyethyl]ami-no] ethoxy]-3-(cyclohexyloxy)-N-[(3-hydroxypropyl) 5 sulfonyl]-4-biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.31-1.63 (6H, m), 1.69 1.77 (2H, m), 1.84-1.91 (2H, m), 1.93-2.00 (2H, m), 3.04-3.30 (4H, m), 3.49-3.58 (4H, m), 4.35 4.44 (2H, m), 4.79-4.85 (1H, m), 5.04 (1H, dd, 10 J=2.2, 10.3Hz), 6.27 (1H, br), 7.12 (2H, d, J=8.8Hz), 7.27 (2H, d, J=8.1Hz), 7.34 (1H, dd, J=1.5, 8.1Hz), 7.41 (1H, d, J=1.5Hz), 7.45 (2H, d, J=8.lHz), 7.74 (1H, d,.J=8.lHz.), 7.75 (1H, d, J=8.4Hz'), 9.03 (1H, br), 9.31 (1H, br), 9.79 (3H, 15 br), 11.1 (1H, br) (-)ESI-MS (m/z): 610 (M-H) (12) 4'-[2-[[(2R)-2-(4-Aminophenyl)-2-hydroxyethyl]aminol] ethoxy]-3-cyclopentyl-N-[(3-hydroxypropyl.)sulfonyl] 20 4-biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.60-1.71 (4H, m), 1.76 1.91 (4H, m), 1.98-2.07 (2H, m), 3.05-3.35 (5H, m), 3.51-3.58 (4H, m), 4.33-4.42 (2H, m), 5.02 (1H, dd, J=2.2, 10.3Hz), 6.25 (1H, br), 7.11 (2H, 25 d, J=8.8Hz), 7.24 (2H, d, J=7.7Hz), 7.42-7.46 (3H, m), 7.53 (1H, dd, J=1.5, 8-.1Hz), 7.62 (1H, d, J=1.5Hz), 7.70 (2H, d, J=8.8Hz), 8.99 (1H, br), 9.23 (1H, br), 9.54 (3H, br), 12.1 (1H, br) (-)ESI-MS (m/z): 580 (M-H)~ 30 (13) 4'-[2-[[(2R)-2-(3-Aminophenyl)-2-hydroxyethyl]amino ethyl]-3-(cyclohexyloxy)-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.30-1.63 (7H, m), 1.68 35 1.77 (2H, m), 1.84-1.91 (2H, m), 1.92-1.99 (2H, WO 2006/033446 PCT/JP2005/017669 45 m), 2.95-3.28 (6H, m), 3.49-3.56 (4H, m), 4.81 (1H, heptuplet, J=4..0Hz), 5.04 (1H, dd, J=2.2, 10.3Hz), 6.38 (1H, br), 7.20 (1H, d, J=8.lHz), 7.28-7.46 (7H, m), 7.72-7.74 (3H, m), 8.97 (1H, 5 br), 9.38 (1H, br), 9.88 (3H, br), 11.2 (1H, br) (-)ESI-MS (m/z): 594 (M-H)~ (14) 3-(Cycloheptyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4' [2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl] 10 4-biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.43-1.61 (6H, m), 1.64 1.73 (2H, m), 1.76-1.91 (4H, m), 2.00-2.09 (2H, m), 3.04-3.42 (4H, m), 3.49-3.56 (4H, m), 4.93 4.98 (1H, m), 5.25 (1H, dd, J=2.9, 9.2Hz), 6.72 15 (1H, br), 7.34-7.36 (2H, m), 7.40 (2H, d, J=8.lHz), 7.72 (1H, d, J=7.7Hz), 7.74 (2H, d, J=8.lHz), 7.90 (1H, dd, J=5.5, 8.1Hz), 8.38 (1H, d, J=7.7Hz), 8.80 (1H, dd, J=1.5, 5.5Hz), 8.86 (1H, d, J=1.5Hz), 9.16 (1H, br), 9.31 (1H, br), 20 11.2 (1H, br s) (-)ESI-MS (m/z): 594 (M-H)~ (15) 4'-[2-[[(2R)-2-(6-Chloro-3-pyridyl)-2-hydroxyethyl] amino]ethyl]-3-(cyclohexyloxy)-N-[(2-hydroxyethyl) 25 sulfonyl]-4-biphenylcarboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.24-2.02 (8H, m), 3.02 3.54 (6H, m), 3.67 (2H, t, J=6.0Hz), 3.84 (2H, t, J=5.8Hz), 4.76-4.87 (1H, m), 5.08-5.16 (1H, m), 6.48 (1H, br s), 7.32-7.44 (4H, m), 7.57 (1H, d, 30 J=8.5Hz), 7.67-7.80 (3H, m), 7.91 (1H, dd, J=2.3, 8.0Hz), 8.46 (1H, d, J=2.OHz), 9.07 (1H, br s), 9.31 (1H, br s), 11.10 (1H, s) (-)ESI-MS (m/z): 600 (M-H)~ 35 (16) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-N- WO 2006/033446 PCT/JP2005/017669 46 [(3-hydroxypropyl)sulfonyl]-3-isobutoxy-4-biphenyl carboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.04 (6H, d, J=7.OHz), 1.80-1.94 (2H, m), 2.03-2.17 (1H, m), 2.99-3.30 5 (6H, m), 3.46-3.59 (4H, m), 4.03 (2H, d, J=6.OHz), 4.74 (1H, t, J=5.0Hz), 4.96-5.05 (1H, m), 6.23 (1H, d, J=3.5Hz), 7.30-7.41'(9H, m), 7.67-7.77 (3H, m), 9.16 (1H, br s) (-)ESI-MS (m/z): 553 (M-H)~ 10 (17) 3-(Cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4'-[2 [[(lS,2R)-2-hydroxy-1-methyl-2-phenylethyl]aminol] ethyl]-4-biphenylcarboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 0.97 (3H, d, J=7.OHz), 15 1.33-2.02 (10H, m), 3.07-3.50 (5H, m), 3.66 (2H, t, J=6.OHz), 3.79-3.88 (2H, m), 4.76-4.88 (1H, m), 4.99-5.11 (1H, m), 5.22 (1H, br s), 6.15 (1H, d, J=4.OHz), 7.29-7.45 (9H, m), 7.71-7.81 (3H, m), 8.97 (2H, br s), 11.10 (1H, br s) 20 (-)ESI-MS (m/z): 579 (M-H)~ (18) 3-Cyclopentyl-4'-[2-[[(2R)-2-hydroxy-2-phenylethyl] amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-4 biphenylcarboxamide hydrochloride 25 NMR (200 MHz, DMSO-d 6 , 8): 1.59-2.10 (10H, m), 2.99 3.30 (7H, m), 3.18-3.61 (4H, m), 4.73-4.81 (1H, m), 4.95-5.04 (1H, m), 6.23 (1H, d, J=4.OHz), 7.32-7.58 (9H, m), 7.64-7.71 (3H, m), 8.91 (1H, br s), 9.24 (1H, br s), 12.15 (1H, br s) 30 (-)ESI-MS (m/z): 549 (M-H)~ (19) 3-(Cyclohexyloxy)-N-[(ethylamino)sulfonyl]-4'-[2 [[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4 biphenylcarboxamide dihydrochloride 35 NMR (200vMHz, DMSO-d 6 , 8): 1.09 (3H, t, J=7.OHz), WO 2006/033446 PCT/JP2005/017669 47 1.29-1.81 (7H, m), 1.91-2.04 (2H, m), 2.94-3.46 (8H, m), 4.77-4.90 (1H, m), 5.25-5.34 (1H, m), 7.34-7.42 (4H, m), 7.71-7.80 (3H, m), 7.90-7.99 (2H, m), 8.46 (1H, d, J=8Hz), 8.82-8.89 (2H, m), 5 9.25 (1H, br s), 9.40 (1H, br s), 10.90 (1H, s) (-)ESI-MS (m/z): 565 (M-H)~ (20) 3-(Cyclohexylamino) -4'-[2-[[(2R)-2-hydroxy-2 phenylethyl]amino]ethoxy]-N-[(3-hydroxypropyl) 10 sulfonyl]-4-biphenylcarboxamide dihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.26-1.89 (12H, m), 3.00 3.71 (9H, m), 4.35-4.43 (2H, m), 5.03 (1H, d, J=7.5Hz), 6.82 (1H, d, J=0.5Hz), 6.94 (1H, s), 7.10 (2H, d, J=8..5Hz), 7.25-7.49 (5H, m), 7.70 15 (2H, d, J=8.5Hz), 7.81 (1H, d, J=8.5Hz), 9.00 (1H, br s), 9.26 (1H, brs) (-)ESI-MS (m/z): 594 (M-H) (21) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]aminol]ethoxy]-N 20 [(3-hydroxypropyl)sulfonyl]-3-(isopropylthio)-4 biphenylcarboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.25 (6H, d, J=6.5Hz), 1.85-1.99 (2H, m), 3.11-3.72 (9H, m), 4.32-4.45 (2H, m), 4.75 (1H, br s), 5.03 (1H, d, J=10Hz), 25 6.22 (1H, d, J=3.5Hz), 7.12 (2H, d, J=8.5Hz), 7.31-7.43 (5H, m), 7.53-7.62 (2H, m), 7.71-7.75 (3H, m), 9.00 (1H, br s), 9.26 (1H, br s), 12.11 (1H, br s) (-)ESI-MS (m/z): 57,1 (M-H)~ 30 (22) 4'-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-3 (isopropylthio)-4-biphenylcarboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.25 (6H, d, J=6.5Hz), 35 1.85-1.99 (2H, m), 2.96-3.27 (6H, m), 3.50-3.72 WO 2006/033446 PCT/JP2005/017669 48 (5H, m), 4.75 (1H, br s), 4.99 (1H, d, J=lOHz), 6.35 (1H, d, J=4Hz), 7.34-7.52 (6H, m)., 7.54 7.67 (2H, m), 7.67-7.81 (3H, m), 8.87 (1H, br s), 8.98 (lH, br s), 12.13 (lH, br s) 5 (-)ESI-MS (m/z): 589, 591 (M-H)~ (23) 3-(Cyclohexyloxy)-4'-[3-[[(2R)-2-hydroxy-2 phenylethyl]amino]propyl]-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide hydrochloride 10 NMR (400 MHz, DMSO-d 6 , 6): 1.28-1.65 (6H, m), 1.67 1.79 (2H, -m), 1.83-2.11 (6H, m),,2.72 (2H, t, J=7.6OHz),,2.94-3.04 (3H, m), 3.11-3.19 (1H, m), 3.47-3.59 (4H, m), 4.74 (lH, t, J=4.8Hz), 4.77 4.85 (1H, m), 4.93-5.0 (1H, m), 6.18 (1H, d, 15 J=3.6Hz), 7.23-7.44 (9H, m), 7.67-7.76 (3H, m) (-)ESI-MS (m/z): 593 (M-H)~ (24) 4'-[3-[[(2R)-2-Hydroxy-2-phenylethyl]amino]propyl]-N [(3-hydroxypropyl)sulfonyl]-3-isopropoxy-4 20 biphenylcarboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.37 (6H, d, J=6.OHz), 1.83-1.93 (2H, m), 1.95-2.09 (2H, m), 2.72 (2H, t, J=8.OHz), 2.93-3.05 (3H, m), 3.10-3.19 (1H, m), 3.47-3.60 (4H, m), 4.75 (1H, t, J=5.2OHz), 25 4.91-5.03 (2H, m), 6.18 (1H, d, J=4Hz), 7.29=7.44 (9H, m), 7.67-7.73 (3H, m) (-)ESI-MS (m/z): 553 (M-H)~ (25) 4'-[3-[[(2R)-2-Hydroxy-2-phenylethyl]amino]propyl]-N 30 [(3-hydroxypropyl)sulfonyl]-3-isobutyl-4-biphenyl carboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 6): 0.87 (6H, d, J=6.4Hz), 1.79-1.93 (3H, m), 1.95-2.08 (2H, m), 2.65-2.77 (4H, m), 2.93-3.04 (3H, m), 3.09-3.19 (1H, m), 35 3.47-3.59 (4H, m), 4.70-4.82.(1H, m), 4.91-5.01 WO 2006/033446 PCT/JP2005/017669 49 (1H, m), 6.14-6.21 (1H, m), 7.27-7..43 (7H, m), 7.50-7.69 (5H, m), 12.11 (1H, s) (-)ESI-MS (m/z): 551 (M-H)~ 5 (26) 3-Cyclopentyl-4'-[3-[[(2R)-2-hydroxy-2-phenylethyl] amino]propyl]-N-[(3-hydroxypropyl)sulfonyl]-4 biphenylcarboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.52-2.20 (12H, m), 2.71 (2H, t, J=7.53Hz), 2.87-3.29 (5H," m), 3.45-3.66 10 (4H, m), 4.69-4.86 (1H, m), 4.89-5.05 (1H, m), 6.18 (1H, d, J=4.02Hz), 7.25-7.70 (12H, m) (-)ESI-MS (m/z): 563 (M-H)~ (27) 4'-[3-[[(2R)-2-(4-Aminophenyl)-2-hydroxyethyl]aminol 15 propyl]-3-(cyclohexyloxy)-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.28-1.64 (6H, m), 1.67 1.79 (2H, m), 1.82-2.11 (6H, m), 2.72 (2H, t, J=7.6Hz), 2.89-3.19 (4H, m), 4.76-4.86 (1H, m), 20 4.95-5.04 (1H, m), 7.23-7.50 (8H, m), 7.65-7.78 (3H, m) (-)ESI-MS (m/z): 608 (M-H)~ (28) 4'-[3-[[(2R)-2-(4-Aminophenyl)-2-hydroxyethyl]amino] 25 propyl]-3-cyclopentyl-N-[(3-hydroxypropyl)sulfonyl] 4-biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.41-1.71 (4H, m), 1.75 1.93 (4H, m), 1.96-2.10 (4H, m), 2.71 (2H, t, J=7.32Hz), 2.92-3.04 (3H, m), 3.07-3.19 (1H, m), 30 3.26-3.36 (1H, m), 3.49-3.60 (4H, m), 4.95-5.01 (1H, m), 7.23-7.58 (8H, m), 7.60-7.71 (3H, m) (-)ESI-MS (m/z): 578 (M-H)~ (29) 4'-[3-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] 35 amino propyl]-N-[(3-hydroxypropyl)sulfonyl]-3- WO 2006/033446 PCT/JP2005/017669 50 isopropoxy-4-biphenylcarboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.37 (6H, d, J=5.9Hz), 1.84-1.93 (2H, m), 1.95-2.07 (2H, m), 2.72 (2H, t, J=7.5Hz), 2.91-3.07 (3H, m), 3.14-3.24 (1H, 5 m), 3.49-3.58 (4H, m), 4.92-5.03 (2H, m), 6.33 (1H, br s), 7.32-7.52 (8H, m), 7.68-7.73 (3H, m), 11.21 (1H, s) (-)ESI-MS (m/z): 587 (M-H) 10 (30) 3-(Cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4' [3-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl] 4-biphenylcarboxamide dihydrochloride NMR (400 MHz, DMSO-d 6 ,'8): 1.28-1.65 (6H, m), 1.67 1.79 (2H, m), 1.81-2.13 (6H, m), 2.73 (2H, t, 15 J=7.68Hz), 2.90-3.05 (2H, m), 3.10-3.23 (1H, m), 3.27-3.38 (1H, m), 3.47-3.60 (4H, m), 4.76-4.86 (1H, m), 5.22-5.30 (1H, m), 7.32-7.44 (4H, m), 7.67-7.76 (3H, m), 7.91-7.98 (1H, m), 8.44 (1H, d, J=8.05Hz), 8.79-8.89 (2H, m), 11.2 (1H, s) 20 (-)ESI-MS (m/z): 594 (M-H)~ (31) N-[(3-Hydroxypropyl)sulfonyll-4'-[3-[[(2R)-2-hydroxy 2-(3-pyridyl)ethyl]amino]propyll-3-isobutoxy-4 biphenylcarboxamide dihydrochlioride 25 NMR (400 MHz, DMSO-d 6 , 8): 1.04 (6H, d, J=7Hz), 1.83 1.91 (2H, m), 1.99-2.13 (3H, m), 2.73 (2H, t, J=7.5Hz), 2.95-3.03 (2H, m), 3.12-3.22 (1H, m), 3.28-3.37 (1H, m), 3.47-3.58 (4H, m), 4.03 (2H, d, J=6.2Hz), 5.23-5.28 (1H, m), 7.33-7..39 (4H, 30 m), 7.67-7.74 (3H, m), 7.91-7.97 (1H, m), 8.43 (1H, d, J=8Hz), 8.79-8.89 (2H, m), 11.21(1H, s) (-)ESI-MS (m/z): 568 (M-H)~ (32) N-[(3-Hydroxypropyl)sulfonyl]-4'-[3-[[(2R)-2-ydroxy 35 2-(3-pyridyl)ethyl]amino]propyl]-3-isopropoxy- 4

-

WO 2006/033446 PCT/JP2005/017669 51 biphenylcarboxamide dihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.37 (6H, d, J=6Hz), 1.81 2.11 (4H, m), 2.73 (2H, t, J=7.3Hz), 2.9-3.41 (4H, m), 3.46-3.61 (4H, m), 4.91-5.05 (1H, m), 5 5.19-5.31 (1H, m), 7.31-7.43 (4H, m), 7.66-7.76 (3H,. m), 7.89-7.99 (1H, m), 8.44 (1H, d, J=8Hz), 8.78-8.89 (2H, m), 11.2 (1H, s) (-)ESI-MS (m/z): 554 (M-H) 10 Example 6 A mixture of 3-[[[[4'-[2-[(tert-butoxycarbonyl)[(2R) 2-(6-chloro-3-pyridyl)-2-hydroxyethyl]amino]aethoxy]-3 (cyclohexyloxy) -4-biphenylyl] carbonyl]amino] sulfonyl] propyl acetate (311 mg), 10% palladium on activated carbon 15 (50% wet, 62 mg), ammonium formate (253 mg), methanol (6.2 ml) and water (6.2 ml) was refluxed for 3 hours. After cooling to room temperature, the catalyst was removed by filtration and washed with methanol. The filtrate was concentrated in vacuo and the residue was chromatographed 20 on silica gel (eluent: hexane/ethyl acetate) to give 3 [[[[4'-[2-(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3 pyridyl)ethyl]amino]ethoxy]-3-(cyclohexyloxy)-4 biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (156 mg) as a white solid. 25 (-)ESI-MS (m/z): 738 (M-H)~ Example 7 To a solution of 3-[[[[4'-[2-[(tert-butoxycarbonyl) [(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethoxy]-3 30 (cyclohexyloxy)-4-biphenylyl]carbonyllamino]sulfonyl] propyl acetate (152 mg) in methanol (1.52 ml) and tetrahydrofuran (0.76 ml) was added 1N sodium hydroxide (0.616 ml) and the mixture was stirred at room temperature for 4 hours. The mixture was quenched by the addition of 35 1N hydrochloric acid (0.616 ml) and the solvent was WO 2006/033446 PCT/JP2005/017669 52 concentrated in vacuo. The residual solid was dissolved in chloroform/methanol (4/1, 10 ml) and dried over magnesium sulfate. Filtration followed by evaporation gave a white solid (161 mg) which was chromatographed on 5 silica gel (eluent: hexane/ethyl acetate) to give tert butyl [2-[[3'-(cyclohexyloxy)-4'-[[[(3-hydroxypropyl) sulfonyl]amino]carbonyl]-4-biphenylyl]oxyethyl][(2R)-2 hydroxy-2-(3-pyridyl)ethylcarbamate (135 mg) as a white solid. 10 (-)ESI-MS (m/z): 696 (M-H) Example 8 A mixture of tert-butyl [2-[3'-(cyclohexyloxy)-4' [[[(3-hydroxyporpyl)sulfonyl]amino]carbonyl]-4 15 biphenylyl]ethyl][(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl] carbamate (234 mg), iron powder (54 mg), ammonium chloride (8.6 mg),' ethanol (3.51 ml) and water (1.17 ml) was refluxed for 50 minutes. After cooling to room temperature, the mixture was filtered through a Celite pad 20 and washed with ethyl acetate (20 ml). The filtrate was washed with brine (20 ml) and dried over magnesium sulfate. Filtration followed by evaporation gave a crude product (217 mg) which was chromatographed on silica gel (eluent: hexane/ethyl acetate=1/2 to 1/3) to give tert-butyl [(2R) 25 2-(4-aminophenyl)-2-hydroxyethyl][2-[3'-(cyclohexyloxy) 4'-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-4 biphenylyl]ethyl]carbamate (136 mg) as a yellow solid. (-)ESI-MS (m/z): 694 (M-H)~ 30 Example 9 The following compounds were obtained according to a similar manner to that of Example 8. (1) tert-Butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][2 35 [4'-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]- 3

'-

WO 2006/033446 PCT/JP2005/017669 53 isobutyl-4-biphenylyl]ethyl]carbamate (-)ESI-MS (m/z): 652 (M-H)~ (2) tert-Butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][2 5 [3' -cyclopentyl-4 ' - [ [[(3-hydroxypropyl)sulfonyl] amino]carbonyl]-4-biphenylyl]ethyl]carbamate (-)ESI-MS (m/z): 664 (M-H) (3) tert-Butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][2 10 [[3'-(cyclohexyloxy)-4'-[[ [(3-hydroxypropyl) sulfonyl]amino]carbonyl]-4-biphenylyl]oxy]ethyl] carbamate (-)ESI-MS (m/z): 710 (M-H)~ 15 (4) tert-Butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][2 [[3'-cyclopentyl-4'-[[[(3-hydroxypropyl)sulfonyl] amino]carbonyl]-4-biphenylyl]oxy]ethyl]carbamate (-)ESI-MS (m/z): 680 (M-H) 20 (5) tert-Butyl ['(2R)-2-(3-aminophenyl)-2-hydroxyethyl][2 [3'-(cyclohexyloxy)-4'-[[[(3-hydroxypropyl)sulfonyl] amino]carbonyl]-4-biphenylyl]ethyl]carbamate (6) tert-Butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][3 25 [3'-(cyclohexyloxy)-4'-[[[(3-hydroxypropyl)sulfonyl] amino]carbonyl]-4-biphenylyl]propyl]carbamate (-)ESI-MS (m/z): 708 (M-H)~ (7) tert-Butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][3 30 [3' -cyclopentyl-4' - [ [ [ (3-hydroxypropyl) sulfonyl] amino]carbonyl]-4-biphenylyl]propyl]carbamate (-)ESI-MS (m/z): 678 (M-H) Example 10 35 A mixture of tert-butyl [2-[4'-[[[[2--(benzyloxy)- WO 2006/033446 PCT/JP2005/017669 54 ethyl]sulfonyl]amino]carbonyl]-3'-(cyclohexyloxy)-4 biphenylyl]ethyl][(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl] carbamate (215 mg), 10% palladium on activated carbon (50% wet, 645 mg), ammonium formate (845 mg), methanol (6.45 5 ml) and water (0.65 ml) was refluxed for 20 minutes. After cooling to room temperature, the catalyst was. removed by filtration and washed with methanol. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel (eluent: hexane/ethyl 10 acetate) to give tert-butyl [(2R)-2-(4-aminophenyl)-2 hydroxyethyl] [2-[3'-(cyclohexyloxy)-4' -[ [ [(2-hydroxy .ethyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl] carbamate (123 mg) as a pale .yellow .solid. (-)ESI-MS (m/z): 680 (M-H)~ 15 Example 11 To a solution of 4'-[2-[(tert-butoxycarbonyl)[(2R) -2 hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]'-3 (cycloheptyloxy)-4-biphenylcarboxylic acid (457 mg) in 20 N,N-dimethylformamide (4.6 ml) was added N,N' carbonyldiimidazole (155 mg) and the mixture was-stirred at room temperature for 1 hour. To the mixture were added 3-(aminosulfonyl)propyl acetate (173 mg) and 1,8 diazabicyclo[5.4.0]undec-7-ene. (0.143 ml) and the mixture 25 was stirred at 120 0 C for 24 hours. After cooling to room temperature, the mixture was quenched by the addition of pH 6.86 buffer (20 ml) and extracted with ethyl acetate (20 ml x 2). The combined extracts were washed with pH 6.86 buffer (40 ml x 2) and brine (40 ml), and dried over 30 magnesium sulfate. Filtration followed by evaporation gave a yellow solid (486 mg) which was chromatographed on silica gel (hexane/ethyl acetate) to give 3-[[[[4'-[2 [(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridyl)ethyl] amino]ethyl]-3-(cycloheptyloxy)-4-biphenylyl]carbonyl] 35 amino]sulfonyl]propyl acetate (276 mg) as a pale yellow WO 2006/033446 PCT/JP2005/017669 55 solid. (-)ESI-MS (m/z): 736 (M-H)~ Example 12 5 The following compound was obtained according to a similar manner to that of Example 7. tert-Butyl [2-[3'-(cycloheptyloxy)-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl][(2R) 10 2-hydroxy-2-(3-pyridyl)ethyl]carbamate (-)ESI-MS (m/z): 694 (M-H)~ Example 13 To a solution of 4'-[2-[(tert-butoxycarbonyl)[(2R)-2 15 (6-chloro-3-pyridyl)-2-(tetrahydro-2H-pyran-2-yloxy) ethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylic acid (180 mg) in N,N-dimethylformamide (1 ml) were added 2-(aminosulfonyl)ethyl acetate (205 mg), N,N dimethylaminopyridine (65 mg) and 1-[3-(dimethylamino) 20 propyl]-3-ethylcarbodiimide hydrochloride (61 mg) at room temperature and the mixture was stirred at the same temperature for 4 days. The mixture was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium 25 sulfate and evaporated under reduced pressure to give an acylsulfonamide product. To a solution of the above product in methanol (3 ml) was added 4-methylbenzene sulfonic acid (30 mg) at room temperature and the mixture was stirred at the same temperature overnight. The 30 mixture was portioned into a mixture of ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chlomatography on silica gel (chloroform/methanol=95/5) to 35 give tert-butyl [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxy- WO 2006/033446 PCT/JP2005/017669 56 ethyl] [2- [ 3' -(cyclohexyloxy) -41'- [ [[(2-hydroxyethyl) sulfonyl]aminolcarbonyl]-4-biphenylyl]ethyllcarbamate (49 mg). (+)ESI-MS (m/z): 724 (M+Na)+ 5 Example 14 The following compound-was obtained according to a similar manner to that of Example 6. 10 tert-Butyl [2-[3'-(cyclohexyloxy)-4'-[[[( 2 hydroxyethyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl] [(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (+)ESI-MS (m/z): 668 (M+H)+ 15 Example 15 To a solution of tert-butyl [2-(4-bromophenyl)ethyl] [(2R)-2-hydroxy-2-(3-pyridyl)ethyl].carbamate (331 mg) in 1,4-dioxane (3.3 ml) were added [4-[[[,(3-hydroxypropyl) sulfonyl]amino]carbonyl]-3-isopropoxyphenyllboronic acid 20 (325 mg), tetrakis(triphenylphosphine)palladium (91 mg) and aqueous solution of sodium carbonate (2M, 1.4 ml), and the mixture was stirred at 80 0 C for 3 hours under nitrogen. The mixture was portioned into a mixture of ethyl acetate and water. The organic layer was separated, washed with 25 brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/methanol 100/3) to give tert-butyl [2-[4'-[[ [(3-hydroxypropyl) sulfonyl]amino]carbonyl]-3'-isopropoxy-4-biphenylyl] 30 ethyl] [ (2R) -2-hydroxy-2- (3-pyridyl)ethyl]carbamate (108 mg). (+)ESI-MS (m/z): 664 (M+Na)+ Example 16 35 The following compounds were obtained according to a WO 2006/033446 PCT/JP2005/017669 57 similar manner to that of Example 11. (1) tert-Butyl [(2R)-2-hydroxy-2-phenylethyl][2-[4' [[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3' 5 isobutoxy-4-biphenylyl]ethyl]carbamate (+)ESI-MS (m/z): 677 (M+Na)+ (2) tert-Butyl [2-[3'-cyclopentyl-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl] 10 [(2R)-2-hydroxy-2-phenylethyl]carbamate (+)ESI-MS (m/z): 673 (M+Na)+ (3) 3-[[[[4'-[3-[(tert-Butoxycarbonyl)[(2-R)-2-hydroxy-2 (3-pyridyl)ethyl]amino]propyl]-3-isobutoxy-4 15 - biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (-)ESI-MS (m/z): 710 (M-H)~ (4) 3-[[[[4'-[3-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2 (3-pyridyl)ethyl]amino]propyl]-3-isopropoxy-4 20 biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (-)ESI-MS (m/z): 696.(M-H)~ (5) Methyl 3-[[[[4'-[2-[(tert-butoxycarbonyl)[(2R)-2 hydroxy-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy) 25 4-biphenylyl]carbonyl]amino]sulfonyl]propanoate (-)ESI-MS (m/z): 707 (M-H)~ (6) 4-[[[[4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2 phenylethyl]amino]ethyl]-3-(cyclohexyloxy)-4 30 biphenylyl]carbonyl]amino]sulfonyl]butyl acetate (-)ESI-MS (m/z): 735 (M-H)~ Example 17 The following compounds were obtained according to a 35 similar manner to that of Example 1.3.

WO 2006/033446 PCT/JP2005/017669 58 (1) tert-Butyl [2-[3'-(cyclohexyloxy)-4'-[[[(2 hydroxyethyl)sulfonyllamino]carbonyl]-4-biphenylyl] ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate 5 (+)ESI-MS (m/z): 689 (M+Na)+ (2) tert-Butyl [2-[3'-(cyclohexyloxy)-4'-[[[(2-hydroxy ethyl)sulfonyl amino]carbonyl]-4-biphenylyl]ethyl] [(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]carbamate 10 -(+)ESI-MS (m/z): 703 (M+Na)+ Example 18 To a solution of tert-butyl [2-.[4'-(aminosulfonyl) 3'-(cyclohexyloxy)-4-biphenylyllethyl][(2R)-2-phenyl-2 15 (tetrahydro-2H-pyran-2-yloxy)ethyl]carbamate (188 mg) in N,N-dimethylformamide (1 ml) were added 4-[(tert butoxycarbonyl)amino]butanoic acid (146 mg), N,N dimethylaminopyridine (40.6 mg) and 1-[3-(dimethylamino) propyl.]-3-ethylcarbodiimide hydrochloride (149 mg) at room 20 temperature and the mixture was stirred at the same temperature for 3 days. The mixture was diluted with ethyl acetate, and washed with aqueous sodium bicarbonate solution, 0.1N hydrochloric acid and brine. The organic layer was dried over sodium sulfate and evaporated under 25 reduced pressure to give an acylsulfonamide product. To a solution of the product in methanol (3 ml) was added 4 methylbenzenesulfonic acid (36 mg) at room temperature and the mixture was stirred at the same temperature for 2 days. The mixture was diluted with ethyl acetate, and washed 30 with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=6/4) to give tert-butyl [2-[4' [[[4-[(tert-butoxycarbonyl)amina]butanoyl]amino]sulfonyl] 35 3'-(cyclohexyloxy)-4-biphenylyl]ethyl][(2R)-2-hydroxy-2- WO 2006/033446 PCT/JP2005/017669 59 phenylethyl]carbamate (117 mg). (+)ESI-MS (m/z): 802 (M+Na)+ Example 19 5 To a solution of tert-butyl [2-[4'-[[[4-[(tert butoxycarbonyl)amino]butanoyllamino]sulfonyl]-3' (cyclohexyloxy)-4-biphenylyllethyl][(2R)-2-hydroxy-2 phenylethyllcarbamate (110 mg) in ethyl acetate (1 ml) was added hydrogen chloride in ethyl acetate (4N, 1 ml) at 10 room temperature and the mixture was stirred at the same temperature for 6 hours. The mixture was filtered to collect the precipitate and the precipitate was washed with ethyl acetate/hexane (1:1). The precipitate was dried under reduced pressure to give 4-amino-N-[[3 15 (cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2-phenylethyl] amino]ethyl]-4-biphenylyl sulfonyl]butanamide dihydrochloride (85 mg). NMR (200 MHz, DMSO-d 6 , 8): 1.25-1.98 (12H, m), 2.36 (2H, t, J=7.3Hz), 2.64-2.77 (2H, m), 2.99-3.28 20 (6H, m), 4.76-4.85 (1H, m), 4.97-5.07 (IH, m), 6.24 (1H, d, J=4.OHz), 7.3-7.43 (9H, m), 7.73 (2H, d,.J=8.5Hz), 7.88 (1H, d, J=8.OHz), 7.98 (2H, br s), 8.98 (1H, br s), 9.41 (1H, br s), 11.94 (1H, br s) 25 (-)ESI-MS (m/z): 578 (M-H)~ Example 20 The following compound was obtained according to a similar manner to that of Example 18. 30 tert-Butyl [2-[4'-[[[[(tert-butoxycarbonyl)amino] acetyl]amino]sulfonyl]-3'-(cyclohexyloxy)-4-biphenylyl] ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (+)ESI-MS (m/z): 774 (M+Na)+ 35 WO 2006/033446 PCT/JP2005/017669 60 Example 21 The following compounds were obtained according to a similar manner to-that of Example 19. 5 (1) 2 -Amino-N-[[3-(cyclohexyloxy)-4'-[2-[[(2R)- 2 -hydroxy 2-phenylethyl]amino]ethyl]-4-biphenylyl]sulfonyl] acetamide dihydrochloride NMR (200 MHz,- DMSO-d 6 , 8): 1.24-1.98 (10H, m), 2.99 3.28 (6H, m), 3.65 (2H, br s), 4.74-4.87 (1H, m), 10 4.99-5.08 (1H, m), 6.25 (1H, br s), 7.3-7.45 (9H, m), 7.72 (2H, d, J=8.OHz), 7.93 (1H, d, J=8.5Hz), 8.26 (3H, br s);, 8.99 (1H, br s), 9.51 (1H, br s), 12.52 (1H, br s) (-)ESI-MS (m/z): 550 (M-H)~ 15 (2) 3 -[[[[3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2 phenylethyl]amino]ethyl]-4-biphenylyl]carbonyl] amino sulfonyl propanoic acid hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.2-2.2 (10H, m), 2.74 (2H, 20 t, J=7.2Hz), 3.0-3.4 (6H, m), 3.75 (lH, t, J=7.2Hz), 4.7-4.85 (1H, m), 4.9-5.0 (1H, m), 6.22 (lH, d, J=3.6Hz), 7.3-7.4 (10H, m), 7.72 (2H, dd, J=2.1,.8.lHz) 25 (3) 3- (Cyclohexyloxy) -N- [ (3-hydroxy-3-methylbutyl) sulfonyl] -4' -[2- [ [(2R) -2-hydroxy-2-phenylethyl] amino]ethyl] -4-biphenylcarboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.11 (1H, s), 1.12-2.0 (12H, m), 2.98-3.06 (2H, m), 3.15-3.42 (6H, m), 30 3.51-3.57 (2H, m), 4.55 (1H, s), 4.75-4.82 (1H, m), 4.9.1-4.94 (1H, m), 6.21 (1H, d, J=1.7Hz), 7.3-7.4Z (10H, m), 7.73 (2H, d, J=4.lHz) (-)ESI-MS (m/z): 607 (M-H) 35 (4) N-[(3-Amino-3-oxopropyl)sulfonyl]-3-(cyclohexyloxy)- WO 2006/033446 PCT/JP2005/017669 61, 4'-[2-[ [ (2R)-2-hydroxy-2-phenylethyl]amino]ethyll- 4 biphenylcarboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.38-1.72 (10H, m), 2.3 2.7 (2H, m), 2.6-2.9 (2H, m), 2.9-3.2 (2H, m), 5 3.3-3.5 (4H, m), 4.8-4.9 (1H, m), 4.92-4.96 (1H, m), 6.22 (1H, d, J=3.4Hz), 7.03 (1H, s), 7.31 7.41 (8H, m), 7.52 (1H, s), 7.73 (2H, d, J=11.3Hz) (+)ESI-MS (m/z): 594 (M+H)+ (free) 10 (5) 3-(Cyclohexyloxy)-N-[(4-hydroxybutyl)sulfonyl]- 4 '-[2 [[(2R) -2-hydroxy-2-phenylethyl]amino]ethyl] -4 biphenylcarboxamide hydrochloride NMR (400 MHz, DMSO-d 6 , 8): 1.32-2.00 (14H, m), 3.06 15 3.65 (10H, m), 4.02 (1H, t, J=6.lHz), 4.78-4.82 (1H, m), 4.99 (1H, d, J=9.4Hz), 6.2-6.23 (1H, m), 7.3-7.41 (10H, m), 7.7-7.74 (2H, m), 8.88 (lH, br s), 9.21 (1H, br s) (-)ESI-MS (m/z): 593 (M-H)~ 20 Example 22 The following compound was obtained according to a similar manner to that of Example 2 followed by a similar manner to that of Example 3. 25 4-[(7S)-7-[[(2R)-2-(4-Chlorophenyl)-2-hydroxyethyll amino]-5,6,7,8-tetrahydro-2-naphthalenyl]-N-[(3-hydroxy propyl)sulfonyl]benzamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.4-2.4 (8H, m), 2.7-3.8 30 (6H, m), 4.11 (1H, m), 5.06 (1H, m), 6.34 (1H, m), 7.25 (1H, d, J=8.OHz), 7.3-7.5 (6H, m), 7.80 (2H, d, J=8.OHz), 8.02 (2H, 'd, J=8.OHz) ESI-MS (m/z): 542 (M+H) 35 Example 23 WO 2006/033446 PCT/JP2005/017669 62 To a solution of 4'-[2-[(tert-butoxycarbonyl)[(2R)-2 (3-chlorophenyl)-2-hydroxyethyl amino]ethyl]-3 (isopropylthio)-4-biphenylcarboxylic acid (150 mg) in tetrahydrofuran (1.5 ml) was added N,N' 5 carbonyldiimidazole (64 mg) and stirred at room temperature for 30 minutes. To the mixture were added 3 (aminosulfonyl)propyl acetate (67 mg) and 1,8 diazabicyclo[5.4.0]-7-undecene (55 il) and stirred at room temperature, and then stirred at 50 0 C for 3 hours. The 10 reaction mixture-was poured into 0.1N hydrochloric acid and ethyl acetate and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 3-[[[[4'-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chloro 15 phenyl)-2-hydroxyethyl~amino]ethyl]-3-(isopropylthio)-4 biphenylylicarbonyl]amino]sulfonyl]propyl acetate (72 mg). To a solution of the product (72 mg) in methanol (2.0 ml) and tetrahydrofuran (2.0 ml) was added sodium hydroxide aqueous solution (1N, 532 lU) and stirred at room 20 temperature for 10 minutes. To the mixture was added hydrochloric acid aqueous solution (lN, 532 Rl) and diluted with ethyl acetate. The solution was poured into water and ethyl acetate and the organic layer was separated. The organic layer was washed with water and 25 brine,-dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography to give tert-butyl [(2R)-2-(3-chloro phenyl)-2-hydroxyethyl][2-[4'-[[[(3-hydroxypropyl) sulfonyl]amino]carbonyl]-3'-(isopropylthio)-4-biphenylyl] 30 -ethyl]carbamate (49 mg). (-)ESI-MS (m/z): 689, 691 (M-H)~ Example 24 The following compound was obtained according to a 35 similar manner to that of Example 23.

WO 2006/033446 PCT/JP2005/017669 63 tert-Butyl [(2R)-2-hydroXY-2-phenylethyl][2-[3' (isopropylthio)-4'-[[[(2-methoxyethyl)sulfonyl]amino] carbonyl]-4-biphenylyl]ethyl]carbamate. 5 (-)ESI-MS (m/z): 655 (M-H) Example 25 To a solution of tert-butyl [(2R)-2-hydroxy-2 phenylethyl][2-[3'-(isopropylthio)-4'-[[[(2-methoxyethyl) 10 sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl]carbamate (3.92 g) in ethyl acetate (20 ml) was added hydrogen chloride ethyl acetate solution (4M, 20 ml) and stirred at room temperature overnight. The resulting solid was collected by filtration and dried to give 4'-[2-[[(2R)-2 15 hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-N [(2-methoxyethyl)sulfonyl]-4-biphenylcarboxamide hydrochloride (3.15 g). NMR (200 MHz, DMSO-d 6 , 8): 1.26 (6H, d, J=6.6Hz), 3.06-3.28 (6H, m), 3.28 (3H, s), 3.61-3.78 (1H, 20 m), 3.78 (4H, s), 4.97-5.03 (1H,m), 6.23 (1Hj d, J=3.6Hz), 7.31-7.42 (7H, m), 7.55-7.64,(2H, m), 7.70-7.74 (3H, m), 8.91 (1H, br s), 9.25 (1H, br s), 12.2 (1H, br s) (-)ESI-MS (.m/z): 555 (M-H)~ 25 Example 26 To a solution of tert-butyl [(2R)-2-hydroxy-2-phenyl' ethyl][2-(4-iodophenoxy)ethyl]carbamate (250 mg) and [3 (cyclohexylamino)-4- [[[(3-hydroxypropyl)sulfonyl]amino] 30 carbonyl]phenyl]boronic acid (258 mg) in toluene (3.0 ml) and ethanol (750 Rl) were added 1',1' bis(diphenylphosphino)ferrocene (29 mg), sodium carbonate aqueous solution (2M, 830 Rl) and [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium (38 mg) 35 at room temperature under nitrogen and stirred at 75 0 C for WO 2006/033446 PCT/JP2005/017669 64 2 hours. The reaction mixture was poured into 0.5N hydrochloric acid (20 ml) and ethyl acetate (20 ml), added active carbon and stirred at room temperature for 30 minutes. The mixture was filtered and separated the 5 organic layer. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified with silica gel column chromatography to give tert-butyl [2-[[3'-(cyclohexyl amino)-4'-[[[(3-hydroxypropyl)sulfonylamino]carbonyl]-4 10 biphenylylloxy]ethyl][(2R)-2-hydroxy-2-phenylethyl] carbamate (127 mg). (-)ESI-MS (m/z): 694 (M-H)~ Example 27 15 The following compounds were obtained according to a similar manner to that of Example 26. (1) 3-[[[[4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-hydroxy-2 phenylethyl]amino]ethoxy]-3-(isopropylthio)-4 20 biphenylyl]carbonyl]amino]sulfonyl propyl acetate (-)ESI-MS (m/z): 713 (M-H)~ (2) tert-Butyl [(2R)-2-hydroxy-2-phenylethyl][2-[[4' [[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3' 25 (isopropylthio)-4-biphenylylloxy]ethyl]carbamate (-)ESI-MS (m/z): 671 (M-H) (3) 3-[[[[4'-[2-[(tert-Btoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3 30 (cyclohexyloxy)-4-biphenylyl]carbonyl]amino] sulfonyl]propyl acetate (-)ESI-MS (m/z): 755 (M-H)~ (4) 3-[[[[4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-(3 35 fluorophenyl)-2-hydroxyethyl]amino]ethyl]-3- WO 2006/033446 PCT/JP2005/017669 65 (cyclohexyloxy)-4-biphenylyl]carbonyl]amino] sulfonyl]propyl acetate (+)ESI-MS (m/z): 763 (M+Na)+ 5 Example 28 The mixture of 3-[[[[4'-[2-[(tert-butoxycarbonyl) [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3 (cyclohexyloxy)-4-biphenylyl]carbonyl]amino]sulfonyl] propyl acetate (269 mg) in hydrogen chloride methanol 10 solution (10%, 2.7 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue -was recrystallized from aqueous ethanol (50%) to give 4'-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxy ethyl]amino]ethyl]-3- (cyclohexyloxy)-N-[(3-hydroxypropyl) 15 sulfonyl]-4-biphenylcarboxamide hydrochloride (161 mg). NMR (200 MHz, DMSO-d 6 , 8): 1.23-2.03 (12H, m), 2.98 3.32 (6H, m), 3.36-3.61 (4H, m), 4.72-4.89 (1H, m), 5.04 (1H, d, J=8.OHz), 6.41 (1H, br s), 7.33-7.48 (8H, m), 7.67-7.82 (3H, m), 8.96 (1H, 20 br s), 9.28 (1H, br s), 11.17 (1H, s) (-)ESI-MS (m/z): 613 (M-H) Example 29 The following compound was obtained according to a 25 similar manner to that of Example 28. 3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-(3-fluorophenyl)-2 hydroxyethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-4 biphenylcarboxamide hydrochloride 30 NMR (200 MHz, DMSO-d 6 , 8): 1.39-1.94 (12H,m), 3.00 3.27 (6H, m), 3.48-3.59 (4H, m); 4.65-4.88 (2H, m), 5.03 (1H, d, J=9.5Hz), 6.36 (1H, d, J=3.5Hz), 7.11-7.51 (8H, m), 7.68-7.79 (3H, m), 9.44 (2H, br s) 35 (-)ESI-MS (m/z): 597 (M-H)~ WO 2006/033446 PCT/JP2005/017669 66 Example 30 To a solution of 3-[[[[4'-[3-[(tert-butoxycarbonyl) [(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]- 3 5 isobutoxy-4-biphenylyl carbonyl]amino]sulfonyl]propyl acetate (108 mg) in methanol (1.08 ml) and tetrahydrofuran (0.324 ml) was added 1N aqueous sodium hydroxide solution (0.455 ml) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated 10 under reduced pressure and the pH value was adjusted to 6.0 with 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate (twice) and the extracts were washed with water and brine, and dried over magnesium sulfate. Filtration followed by evaporation under reduced 15 pressure gave tert-butyl [3-[4'-[[[(3-hydroxypropyl) sulfonyl]amino]carbonyl]-3'-isobutoxy-4-biphenylyl] propyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl carbamate (91.1 mg) as a white solid (foam). (-)ESI-MS (m/z): 668 (M-H)~ 20 Example 31 To a solution of 3-[[[[4'-[3-[(tert-butoxycarbonyl) [(2R)-2-hydroxy-2-(3-pyridyl)ethylamino propyl]-3 isopropoxy-4-biphenylyl]carbonyl]amino]sulfonyl propyl 25 acetate (221 mg) in methanol (2.21 ml) and tetrahydrofuran (1.11 ml) was added 1N sodium hydroxide (0.950 ml) and the mixture was stirred at room temperature for 1 hour. Methanol and tetrahydrofuran were removed by evaporation under reduced pressure and to the residue was added water 30 (50 ml). The mixture was acidified with 1N hydrochloric acid (pH=5.4) and extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with water and brine, and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave tert-butyl [3-[4' 35 [[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3'- WO 2006/033446 PCT/JP2005/017669 67 isopropoxy-4-biphenylyl]propyl][(2R)-2-hydroxy-2-(3 pyridyl)ethyl]carbamate (212 mg) as a white solid. (-)ESI-MS (m/z): 654 (M-H) 5 Example 32 The following compound was obtained according to a similar manner to that of Preparation 3. 3- [[[[4'-[2- [ (tert-Butoxycarbonyl) [(2R) -2-hydroxy-2 10 phenylethyl] amino]ethyl] -3- (cyclohexyloxy) -4-biphenylyl] carbonyl]amino]sulfonyl]propanoic acid NMR (200 MHz, DMSO-d 6 , .): 1.2-1.8 (10H, m), 1.33 (9H, s), 2.6-2.9 (4H, m), 3.0-3.6 (4H, m), 3.75 (2H, t, J=7Hz), 4.62-4.82 (2H, m), 5.45 (1H, br s), 15 7.2-7.4 (9H, m), 7.6-7.73 (3H, m) (+)ESI-MS (m/z): 695 (M+H)+ Example 33 Under a nitrogen atmosphere, methylmagnesium chloride 20 (3.0 M in tetrahydrofuran, 118 ptl) was added to a solution of methyl 3-[[[[4'-[2-[(tert-butoxycarbonyl)[(2R)-2 hydroxy-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy)-4 biphenylyl]carbonyl]amino]sulfonyllpropanoate (50.0 mg) in tetrahydrofuran (1.0 ml) at -78 0 C, and the mixture was 25 stirred at 0*C for 10 minutes. The mixture was poured into sat. ammonium chloride aq. solution and the products were extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica 30 gel column chromatography to give tert-butyl [2-[3' (cyclohexyloxy)-4'-[[[(3-hydroxy-3-methylbutyl)sulfonyl] amino]carbonyl]-4-biphenylyl]ethyl][(2R)-2-hydroxy-2 phenylethyl]carbamate (33.8 mg). (-)ESI-MS (m/z): 707 (M-H)~ 35 WO 2006/033446 PCT/JP2005/017669 68 Example 34 Sodium methoxide (38.1 mg) was added to a solution of methyl 3 -[[[[4'-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy 2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenyl 5 yl]carbonyl]amino]sulfonyl]propanoate (125 mg) 'in formamide (2.0 ml) at room temperature. The mixture was stirred for 1.5 hours at 60*C. The product was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and evaporated in 10 vacuo. The residue was purified by silica gel column chromatography to give tert-butyl [2-[4'-[[[(3-amino-3 oxopropyl)sulfonyl]amino]carbonyl]-3' -(cyclohexyloxy) -4 biphenylyl]ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (22.0 mg). 15 (+)ESI-MS (m/z): 694 (M+H)+ Example 35 1N Sodium hydroxide (575 pl) was added to a solution of 4-[[[[4'-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2 20 phenylethyl] amino] ethyl] -3- (cyclohexyloxy) -4 -biphenylyl] carbonyl]amino]sulfonyl]butyl acetate (212 mg) in methanol (4.24 ml). The mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo. The residue was purified by silica. gel column chromatography 25 to give tert-butyl [2-[3'-(cyclohexyloxy)-4'-.[[[( 4 hydroxybutyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl] [(2R)-2-hydroxy-2-phenylethyl]carbamate (111 mg). (-)ESI-MS (m/z): 695 (M+H)+ 30 Preparation 27 A mixture of 3-pyridinesulfonic acid (10.0 g), phosphorous pentachloride (13.1 g) and phosphoryl chloride (10.0 ml) was stirred at 130 0 C for 3.5 hours. The solution was evaporated and diluted with acetone. The 35 solution was evaporated and poured into water (200 ml) and WO 2006/033446 PCT/JP2005/017669 69 isopropyl ether (400 ml). The organic layer was separated, washed with brine twice, saturated sodium bicarbonate aqueous solution and brine and dried over magnesium sulfate. The solution was evaporated, covered with hexane 5 (20 ml) and added hydrogen chloride in ethyl acetate (4N, 20 ml) dropwise with stirring. The resulting solid was collected by filtration and dried to give 3 pyridinesulfonyl chloride hydrochloride (9.49 g). NMR (200 MHz, DMSO-d 6 , 6): 8.12 (1H, dd, J=5, 8Hz), 10 8.72 (1H, dd, J=1.8, 3Hz), 8.95 (1H, d, J=5.5Hz), 8.99 (1H, d, J=lHz), 14.25 (1H, br s) Preparation 28 To a suspension of 3-pyridinesulfonyl chloride 15 hydrochloride (5.00 g).:in acetone (8.5 ml) was added ammonia aqueous solution (28%, 8.5 ml) at 0 0 C dropwise and stirred at room temperature for 3 hours. The solution was evaporated and poured into water (ca. 10 ml), ethyl acetate (100 ml) and tetrahydrofuran (100 ml). The 20 organic layer was washed with brine twice and the aqueous layer was extracted with ethyl acetate (90 ml) and methanol (10 ml). The combined organic layer was dried over magnesium sulfate, evaporated and crystallized in hexane and ethyl acetate to give 3-pyridinesulfonamide 25 (3.45 g). (+)ESI-MS (m/z):. 159 (M+H)+ Preparation 29 To a suspension of sodium sulfite (41.7 g) in water 30 (40 ml) was added chloroacetonitrile (20.8 ml) and stirred at room temperature for 4 hours. The mixture was evaporated and diluted with methanol. The mixture was diluted with methanol and toluene, evaporated and crystallized from ethanol. The resulting solid was dried 35 at 60 0 C to give sodium cyanomethanesulfonate (53.5 g).

WO 2006/033446 PCT/JP2005/017669 70 (-)ESI-MS (m/z): 120 (M-Na)~ Preparation 30 A mixture of sodium cyanomethanesulfonate (15.0 g), 5 phosphorous pentachloride (21.8 g) and phosphoryl chloride (27.0 ml) was stirred at 70 0 C under nitrogen for 3 hours. The solid was filtered off, and the solution was evaporated to give cyanomethanesulfonyl chloride (8.66 g) as crude oil. This compound was used for next- reaction, 10 without further purification. Preparation 31 A solution of crude cyanomethanesulfonyl chloride (8.66 g) in dichloromethane (52.0 ml) and tetrahydrofuran 15 (13.0 ml) was bubbled with ammonia gas below 10 0 C for 1 hour with stirring. The brown solid was collected by filtration, and eluted with methanol. The solution was. evaporated and the residue was purified with silica gel column chromatography to give 1-cyanomethanesulfonamide 20 (1.36 g). (-)ESI-MS (m/z): 119 (M-H)~ Preparation 32 To a solution of 4'-[2-[(tert-butoxycarbonyl)[(2R)-2 25 phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl] 3-(isopropylthio)-4-biphenylcarboxylic acid (500 mg) in N,N-dimethylformamide (5 ml) was added N,N' carbonyldiimidazole (157 mg) and stirred at room temperature for 30 minutes. To the mixture were added 3 30 pyridinesulfonamide (153 mg) and 1,8-diazabicyclo[5.4.0] 7-undecene (145 pl) and stirred at room temperature for 3 hours. The reaction mixture was poured into 0.1N hydrochloric acid and ethyl acetate and the organic layer was separated. The organic layer was washed with water 35 and brine, dried over magnesium sulfate and concentrated WO 2006/033446 PCT/JP2005/017669 71 in vacuo. The residue was purified with silica gel column chromatography to give tert-butyl [2-[3'-(isopropylthio) 4' - [[(3-pyridylsulfonyl)amino]carbonyl]-4-biphenylyl] ethyl] [ (2R)-2-phenyl-2-(tetrahydro--2H-pyran-2-yloxy) 5 ethyl]carbamate (613 mg). (-)ESI-MS (m/z): 758 (M-H) The following compounds from Preparation 33 to Preparation 35 were obtained according to a similar manner 10 to that of Preparation 32. Preparation 33 tert-Butyl [2-[4'-[[[(cyanomethyl)sulfonyl]amino] carbonyl]-3'-(isopropylthio)-4-biphenylyl]ethyl][(2R)-2 phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]carbamate 15 (-)ESI-MS (m/z): 720 (M-H) Preparation 34 tert-Butyl [(2R)-2-[[tert-butyl(dimethyl)silylloxy] 2-(3-pyridyl)ethyl][2-[3'-(cyclohexyloxy) -4'- [[(3 pyridylsulfonyl)amino]carbonyl] -4-biphenylyllethyll 20 carbamate (-)ESI-MS (m/z): 813 (M-H)~ Preparation 35 tert-Butyl [(2R)-2-[[tert-butyl(dimethyl)silyl]oxy] 2- (3-pyridyl)ethyl], 2- [4'- [ [[(.cyanomethyl)sulfonyl]amino] 25 carbonyl]-3'-(cyclohexyloxy)-4-biphenylyl]ethyl]carbamate (-)ESI-MS (m/z): 776 (M-H) Preparation 36 To a solution of tert-butyl [(2R)-2-(3-chlorophenyl) 30 2-hydroxyethyl][2-[(4-iodophenyl)amino]ethyl]carbamate (200 mg), [3-(cyclohexyloxy)-4-(methoxycarbonyl)phenyl] boronic acid (193 mg), potassium phosphate (246 mg) in ethanol (1.5 ml) was added bis(dicyclohexylamine) palladium(II) acetate (32.9 mg) and the mixture was 35 stirred at 60 0 C for 3 hours under nitrogen atmosphere.

WO 2006/033446 PCT/JP2005/017669 72 After warming to 80'C, the mixture was stirred at the same temperature for 3 hours. To the reaction mixture were added [3-(cyclohexyloxy)-4-(methoxycarbonyl)phenyl]boronic acid (107 mg) and bis(dicyclohexylamine)palladium(II) 5 acetate (10.9 mg) and the mixture was stirred at 80 0 C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through the celite cake. The filtrate was washed with water and brine and dried over magnesium sulfate. 10 Filtration followed by evaporation under reduced pressure gave the crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/6 to 1/2) to give methyl 4'-[[2-[(tert-butoxy carbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino] 15 ethyl]amino]-3-(cyclohexyloxy)-4-biphenylcarboxylate (130 mg) as a white solid. (+)ESI-MS (m/z): 623 (M+H)+, 646 (M+Na)+ Preparation 37 20 To a solution of methyl 4'-[[2-[(tert-butoxy carbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino] ethyl]amino]-3-(cyclohexyloxy)-4-biphenylcarboxylate (125 mg) in methanol (1.750 ml) and tetrahydrofuran (0.900 ml) was added 1N aqueous sodium hydroxide solution (1.05 ml) 25 and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added 1N aqueous sodium hydroxide solution (0.900 ml) and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and to the residue 30 were added ethyl acetate (40 ml) and water (20 ml). The pH value was adjusted to 5.70 by addition of 0.1N hydrochloric acid and the separated organic layer was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation gave 4'-[[2 35 [(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2- WO 2006/033446 PCT/JP2005/017669 73 hydroxyethyl]amino]ethyl]amino]-3-(cyclohexyloxy)-4 biphenylcarboxylic acid (123 mg) as a yellow foam. (-)ESI-MS (m/z): 607 (M-H) 5 Preparation 38 To a solution of methyl 4'-[[2-[(tert-butoxy carbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino] ethyl]amino]-3-(cyclohexyloxy)-4-biphenylcarboxylate (125 mg) in methanol (1.750 ml) and tetrahydrofuran (0.900 ml) 10 was added 1N aqueous sodium hydroxide solution (1.05 ml) and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added 1N aqueous sodium hydroxide solution (0.900 ml) and the mixture was stirred at room temperature for 3 days. The reaction mixture was 15 concentrated under reduced pressure and to the residue were added ethyl acetate (40 ml) and water (20 ml). The pH value was adjusted to 5.70 by addition of 0.1N hydrochloric acid and the separated organic layer was washed with water and brine and dried over magnesium 20 sulfate. Filtration followed by evaporation gave 4'-[[2 [(tert-butoxycarbonyl)[(2R)-2-(-3-chlorophenyl)-2 hydroxyethyl]amino]-ethyl amino]-3-(cyclohexyloxy)-4 biphenylcarboxylic acid (123 mg) as a yellow foam. (+)ESI-MS (m/z): 597 (M+H)+, 620 (M+Na)+ 25 Preparation 39 The following compound was obtained according to a similar manner to that of Preparation 37. 30 4'-[[2-[(tert-Butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl amino ethyl]amino]-3 isobutoxy-4 -biphenylcarboxylic acid (-)ESI-MS (m/z): 582 (M-H)~ 35 Preparation 40 WO 2006/033446 PCT/JP2005/017669 74 To a solution of 6-bromo-1-isopropyl-1H-indole-3 carboxylic acid (1.94 g) in N,N-dimethylformamide (97 ml) were added potassium carbonate (1.43 g) and iodomethane (0.514 ml) at room temperature under nitrogen, and the 5 mixture was stirred at the same temperature for 3.5 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water three times and brine, dried over anhydrous magnesium sulfate 10 and evaporated under reduced pressure. The residue was purified by column chromatography on silica' gel (hexane/ethyl acetate=10/1 to 5/1) to give methyl 6-bromo 1-isopropyl-1H-indole-3-carboxylate.(1.9 g). (+)ESI-MS (m/z): 318, 320 (M+Na)+ 15 Preparation 41 To a solution of methyl 6-bromo-2-naphthoate (5.0 g) in 1,4-dioxane (50 ml) were added 4,4',4' ,4',5,5,5',5' octamethyl-2,2'-bi-1,3,2-dioxaborolane (5.3 g), 20 dichlorobis(triphenylphosphine)palladium(II) (1.3 g) and potassium acetate (4.6 g) at room temperature under nitrogen, and the mixture was stirred at 90 0 C for 2 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The 25 organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: chloroform) to-give methyl 6-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthoate (3.6 g). 30 (+)ESI-MS (m/z): 313, (M+H)+ Preparation 42 The following compound was obtained according to a similar manner to that of Preparation 41. 35 WO 2006/033446 PCT/JP2005/017669 75 Methyl 1-isopropyl- 6 -(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-1H-indole-3-carboxylate (+)ESI-MS (m/z): 366 (M+Na)+ 5 Preparation 43 To a solution of tert-butyl [2-(4-bromophenyl)ethyl] [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (560 mg) and methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)-2-naphthoate (461 mg) in N,N-dimethylformamide (5.6 10 ml) were added [1',1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride dichloromethane complex (151 mg), 1,1'-bis(diphenylphosphino)ferrocene (102 mg) and 2M sodium carbonate (2.0 ml) at room temperature, and the mixture was stirred at 80 0 C for 4 hours. The resulting 15 mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water three times and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by 20 column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 6-[4-[2-[(tert butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxy ethyl]amino]ethylphenyl]-2-naphthoate (514 mg). (+)ESI-MS '(m/z): 582, 584 (M+H)+ 25 Preparation 44 The following compound was obtained according to a similar manner, to that of Preparation 43. 30 Methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino ethyl]phenyl]-1 isopropyl-1H-indole-3-carboxylate (+)ESI-MS (m/z): 613, 615 (M+Na)+ 35 Preparation 45 WO 2006/033446 PCT/JP2005/017669 76 To- a solution of methyl 6-[4-[2-[(tert-butoxy carbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino] ethyliphenyl]-1-isopropyl-1H-indole-3-carboxylate (340 mg) in dichloromethane (5 ml) were added 3,4-dihydro-2H-pyran 5 (0.105 ml) and a catalytic amount of pyridinium p-toluene sulfonate at room temperature under nitrogen, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The 10 organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) to give methyl 6-[4 15 [2-[(,tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2 (tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]phenyl]-1 isopropyl-1H-indole-3-carboxylate (310 mg). (+)ESI-MS (m/z): 697 (M+Na)+ 20 Preparation 46 A mixture of methyl 6-[4-[2-[(tert-butoxycarbonyl) [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl] phenyl]-2-naphthoate (105 mg) and 1N ,sodium hydroxide (0.375 mi) in 1,4-dioxane (1 ml) was stirred at room 25 temperature for 12 hours. To the resulting mixture were added IN hydrochloric acid (0.375 ml) and chloroform methanol (5:1). After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure. The residue was purified by column 30 chromatography on silica gel (chlorofom/methanol=10/1) to give 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-2 naphthoic acid (100 mg). (-)ESI-MS (m/z): 544, 546 (M-H)~ 35 WO 2006/033446 PCT/JP2005/017669 77 Preparation 47 The following compound was obtained according to a similar manner to that of Preparation 46. 5 6-[4-[2-[(tert-Butoxycarbonyl)[(2R)- 2 -(3-chloro phenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino] ethyliphenyl]-1-isopropyl-1H-indole-3-carboxylic acid (-)ESI-MS (m/z): 659, 661 (M-H)~ 10 Preparation 48 To a solution of 6-[4-[2-[(tert-butoxycarbonyl)[(2R) 2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl] amino]ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylic acid (131 mg) in N,N-dimethylformamide (2 mL) was added 15 1,1'-carbonyldiimidazole (35 mg) at room temperature under nitrogen, and the mixture was stirred at the same temperature for 2.5 hours. To this one were added methanesulfonamide (46 mg) and 1,8-diazabicyclo[5.4.0]-7 undecene (72 mg) at room temperature, and the mixture was 20 stirred at 60 0 C for 10 hours. The resulting mixture was poured into 0.1N hydrochloric acid and the aqueous layer was extracted with ethyl acetate. The.organic layer was washed successively with O.1N hydrochloric acid three times and brine, dried over anhydrous magnesium sulfate 25 and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=200/1 to 100/1) to give tert-butyl [(2R)-2-(3-'chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy) ethyl] [2-[4-[-isopropyl-3-[[(methylsulfonyl)amino]-" 30 carbonyl]-1H-indol-6-yl]phenyl]ethyl]carbamate (134 mg). (-)ESI-MS m/z: 736, 738 (M-H)~ Preparation 49 The following compound was obtained according to a 35 similar manner to that of Preparation 48.

WO 2006/033446 PCT/JP2005/017669 78 3-[[[[6-[4-[2-[(tert-Butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino] ethyl]phenyl] -1-isopropyl-1H-indol-3-yl]carbonyl ] amino] 5 sulfonyllpropyl acetate (+)ESI-MS (m/z): 846 (M+Na)+ Preparation 50 The following compound was obtained according to a 10 similar manner to that of Preparation 38. Methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2 (3-pyridyl)ethyl]amino]ethyl]-3-(cyclohexyloxy)-4 biphenylcarboxylate 15 NMR (200 MHz, DMSO-d 6 , 6): 1.17-1.98 (10H, m), 1.27 (9H, s), 2.65-2.81 (2H, m), 3.10-3.55 (4H, m), 3.79 (3H, s), 4.60-4.85 (2H, m), 5.61-5.68 (1H, m), 7.22-7.72 (9H, m), 8.44-8.49 (2H, m) (+)ESI-MS (m/z): 575 (M+H)+ 20 Preparation 51 To a solution of methyl 4'-[2-[(tert-butoxycarbonyl) [(2R) -2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3 (cyclohexyloxy)-4-biphenylcarboxylate in N,N 25 dimethylformamide were added imidazole and tert butyldimethylchlorosilane at room temperature. After stirring at room temperature for 15 minutes and at 35 0 C for 3.5 hours. The reaction mixture was poured into 0.05N hydrochloric acid at room temperature. The products were 30 extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography to give methyl 4'-[2-[(tert butoxycarbonyl)[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2 35 (3-pyridyl)ethyl ] aminolethyl] -3- (cyclohexyloxy) -4- WO 2006/033446 PCT/JP2005/017669 79 biphenylcarboxylate (11.22 g). NMR (200 MHz, DMSO-d 6 , 8): -0.15 (3H, s), 0.00 (3H, s), 0.81 (9H, s), 1.31-1.38 (9H, s), 1.20-1.30 (10H, m), 2.73-2.80 (2H, m), 3.25-3.43 (4H, m), 5 3.38 (3H, s), 4.50-4.80 (1H, m), 4.85-5.11 (1H, m), 7.20-7.71 (9H, m), 8.47-8.52 (2H, m) (+)ESI-MS (m/z): 689 (M+H)+ Preparation 52 10 The following compound was obtained according to a similar manner to that of Preparation 37. 4' -[2-[ (tert-Butoxycarbonyl) [ (2R)-2-[ [tert-butyl (dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl]amino]ethyl]-3 15 (cyclohexyloxy)-4-biphenylcarboxylic acid NMR (200 MHz, DMSO-d 6 , 8): -0.14 (3H, s), 0.01 (3H, s), 0.82 (9H, s), 1.32-1.39 (9H, m), 1.21-1.99 (10H, m), 2.48-2.77 (2H, m), 3.25-3.43 (4H, m), 4.58-1.65 (1H, m), 4.90-5.20 (1H, m), 7.20-7.41 20 (5H, m), 7.58-7.78 (4H, m), 8.47-8.52 (2H, m) (+)ESI-MS (m/z): 675 (M+H)+ Preparation 53 The following compound was obtained according to a 25 similar manner to that of Example 40. Methyl 3-[[[[4'-[2-[(tert-butoxycarbonyl)[(2R)-2 [[tert-butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl] amino]ethyl]-3-(cyclohexyloxy)-4-biphenylyl]carbonyl] 30 amino]sulfonyl propanoate NMR (200 MHz, DMSO-d 6 , 8): -0.14 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.28-1.32 (9H, m), 1.16-1.88 (10H, m), 1.90-2.00 (2H, m), 2.77-2.87 (3H, m), 2.55-3.50 (3H, m), 3.78,(2H, t, J=7.3Hz), 3.33 35 (3H, s), 4.74-4.80 (1H, m), 4.90-5.04 (1H, m), WO 2006/033446 PCT/JP2005/017669 80 7.26-7.42 (5H, m), 7.60-7.72 (4H, m), 8.49-7.82 (2H, m), 11.30 (1H, s) (-)ESI-MS (m/z): 822 (M-H)~ 5 Preparation 54 The following compound was obtained according to a similar manner to that of Preparation 37. 3-[[[[4'-[2-[( tert-Baitoxycarbonyl)[(2R)-2--[[tert 10. butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl]amino] ethyl]-3-(cyclohexyloxy)-4-biphenylyl]carbonyl] amino]sulfonyl]propionic acid NMR (200 MHz, DMSO-d 6 , 8): -0.13 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 0.82-1.13 (9H, m), 1.13-1.80 15 (10H, m), 1.91-1.99 (2H, m), 2.70-2.78 (4H, m), 3.25-3.34 (2H, m), 3.74-3.78 (2H, m), 4.75-4.78 (1H, m), 4.90-5.02 (1H, m), 7.25-7.42 (5H, m), 7.64-7.76 (4H, m), 8.49-8.52 (2H, m) (-)ESI-MS (m/z): 808 (M-H)~ 20 Preparation 55 The following compound was obtained according to a similar manner to that of Example 33. 25 tert-Butyl [(2R)-2-[[tert-butyl(dimethyl)silyl]oxy] 2-(3-pyridyl)ethyl][2-[3'-(cyclohexyloxy)-4'-[[[(3 hydroxy-3-methylbutyl)sulfonyl]amino]carbonyl]-4 biphenylyl]ethyl]carbamate NMR (200 MHz, DMSO-d 6 , 8): -0.14 (3H, s), 0.00 (3H, 30 s), 0.82 (9H, s), 1.11 (6H, s), 1.71-1.21 (9H, m), 1.20-1.8 (10H, m), 1.95-2.05 (2H, m), 2.70 2.9 (2H, m), 3.23-3.60 (6H, m), 4.54 (1H, s), 4.76-4.82 (1H, m), 4.95-5.38 (lH; m), 7.26-7.42 (5H, m), 7.64-7.73 (4H, m), 8.49-8.52 (2H, m), 35 11.10 (1H, s) WO 2006/033446 PCT/JP2005/017669 81 (+)ESI-MS (m/z): 825 (M+H)+ Preparation 56 To a solution of tert-butyl [(2R)-2-[[tert-butyl 5 (dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl][ 2 -[4' [[[(cyanomethyl)sulfonyl]amino]carbonyl] -3' -(cyclohexyl oxy)-4-biphenylyl]ethyl]carbamate (52.9 mg) in dimethyl sulfoxide (1.0 ml) was added potassium carbonate (28.3 mg), 30% aq. hydrogen peroxide solution (100 pl) at 0*C. After 10 stirring for 16 hours at room temperature, 1N hydrochloric acid was added to the reaction mixture. The products were extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated. The residue was purified by preparative thin 15 layer chromatography (chloroform/methanol=95/5) to give' tert-butyl [2-[4'-[[[(2-amino-2-oxoethyl)sulfonyl]amino] carbonyl]-3'-(cyclohexyloxy) -4-biphenylyllethyl][(2R)-2 [[tert-butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl] carbamate (30.0 mg). 20 (-)ESI-MS (m/z): 793 (M-H)~ Preparation 57 The following compound was obtained according to a similar manner to that of Example 40. 25 4-[[[[4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-[[tert butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl]amino]ethyl] 3-(cyclohexyloxy)-4-biphenylyl]carbonyl]amino]sulfonyl] butyl acetate 30 NMR (200 MHz, DMSO-d 6 , 8): -0.15 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.28-1.32 (9H, m), 1.26-2.00 (14H, m), 1.97 (3H, s), 2.75-2.79 (2H, m), 3.24 3.56 (6H, m), 3.98-4.04 (2H, m), 4.76- 4.80 (1H, m), 4.94-5.04 (1H, m), 7.26-7.41 (5H, m), 7.63 35 7.72 (4H, m), 8.49-8.52 (2H, m), 11.18 (1H, s) WO 2006/033446 PCT/JP2005/017669 82 (-)ESI-MS (m/z): 850 (M-2H)~ Preparation 58 The following compound was obtained according to a 5 similar manner to that of Example 35. tert-Butyl [(2R)-2-[[tert-butyl(dimethyl)silyl]6xy] 2-(3-pyridyl)ethyl][2-[3'-(cyclohexyloxy)-4'-[[[(4 hydroxybutyl)sulfonyl]amino]carbonyl]-4-biphenylyl] 10 ethyl]carbamate NMR (200 MHz, DMSO-d 6 , 8): -0.15 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.23-1.28 (9H, m), 1.22-2.10 (14H, m), 2.73-2.80 (2H, m), 3.20-3.58 (8H, m), 4.49 (1H, t, J=5Hz), 4.76-4.80 (1H., m), 4.95 15 5.05 (1H, m), 7.25-7.41 (5H, m), 7.62-7.72'(4H, m), 8.49-8.52 (2H, m), 11.10 (H, s) (-)ESI-MS (m/z): 809 (M-H)~ Preparation 59 20 The following compound was obtained according to a similar manner to that of Preparation 38. Methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-(3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3 25 (cyclohexyloxy)-4-biphenylcarboxylate NMR (200 MHz, DMSO-d 6 , 8): 1.43 (9H, s), 1.20-2.00 (10H, m), 2.64-2.98 (2H, m), 3.02-3.65 (4H, m), 3.83 (3H, s), 4.38-4.48 (1H, m), 4.84-4.91 (1H, m), 7.12-7.52 (10H, m), 7.84 (1H, d, J=8.5Hz) 30 (+)ESI-MS (m/z): 631 (M+Na)+ Preparation 60 The following compound was obtained according to a similar manner to that of Preparation 51. 35 WO 2006/033446 PCT/JP2005/017669 83 Methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-[[tert butyl ( dimethyl) silyl] oxy] -2- (3- chlorophenyl) ethyl ] amino] ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylate NMR (200 MHz, DMSO-d 6 , 8): -0.11 (3H, s), 0.10 (3H, 5 s), 0.87-0.90 (9H, m), 1.39-1.45 (9H, m), 1.35 2.00 (10H, m), 2.72-3.89 (6H, m), 3.89 (3H, s), 4.40-4.43 (1H, m), 5.03-5.07 (1H, m), 7.12-7.38 (8H, m), 7.46-7.50 (2H, m), 7.84 (1H, d, J=8.5Hz) 10 (+)ESI-MS (m/z): 744 (M+Na)+ Preparation 61 The following compound was obtained according to a similar manner to that of Preparation 37. 15 4'- [2- [ (tert-Butoxycarbonyl) ['(2R) -2- [ [tert butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]amino] ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylic acid NMR (200 MHz, DMSO-d 6 , 8): -0.13 (3H, s), 0.00 (3H, 20 s), 0.83 (9H,. s), 1.30-1.34 (9H, m), 1.21-1.99 (10H, m), 2.52-2.80 (2H, m), 3.20-3.49 (4H, m), 4.59-4.65 (1H, m), 4.87-4.99 (1H, m), 7.21-7.70' (11H, m) (-)ESI-MS (m/z): 706 (M-H.)~ 25 Preparation 62 The following compound was obtained according to a similar manner to that of Example 40. 30 tert-Butyl [(2R)-2-[[tert-butyl(dimethyl)silyl]oxy] 2-(3-chlorophenyl)ethyl][2-[4'-[[[(cyanomethyl)sulfonyl] aminolcarbonyl]-3'-(cyclohexyloxy)-4-biphenylyl]ethyl] carbamate NMR (200 MHz, DMSO-d 6 , 5): -0.14 (3H, s), 0.00 (3H, 35 s), 0.83 (9H, s), 1.29-1.34 (9H,,m), 1.20-2.00 WO 2006/033446 PCT/JP2005/017669 84 (10H, m), 2.72-2.81 (2H, m), 3.20-0.48 (4H, m), 4.70-4.76 (1H,.m), 4.88-4.99 (1H, m), 5.24 (2H, s), 7.25-7.43 (8H, m), 7.63-7.68 (3H, m) (-)ESI-MS (m/z): 808 (M-H)^ 5 Preparation 63 The following compound was obtained according to a similar manner to that of Preparation 56. 10 tert-Butyl [2-[4'-[[[(2-amino-2-oxoethyl)sulfonyl] amino]carbonyl] -3'- (cyclohexyloxy) -4-biphenylyl]ethyl] [ (2R) -2-[ [tert-butyl(dimethyl)silyl]oxy]-2-(3 chlorophenyl)ethyl]carbamate NMR (200 MHz, DMSO-d 6 '- ).: -0.13 (3H, s), 0.00 (3H, 15 s), 0.83 (9H, s), 1.29-1.33 (9H, m), 1.20-2.00 (10H, m), 2.52-2.81 (2H, m), 3.20-3.48 (4H, m), 4.35 (2H, s), 4.81-4.99 (2H, m), 7.25-7.84 (11H, m), 11.20 (1H, s) (-)ESI-MS (m/z): 826 (M-H)~ 20 Preparation 64 A mixture of tert-butyl [(2R)-2-(3-chlorophenyl)-2 (tetrahydro-2H-pyran-2-yloxy)ethyl][2-[4-[1-isopropyl-3 [[(methylsulfonyl)amino]carbonyl] -1H-indol-6-yl]phenyl] 25 ethyl]carbamate (132 mg), 10% hydrogen chloride in methanol (2 ml) and 4N hydrogen chloride in 1,4-dioxane (2 ml) was stirred at room temperature for 12 hours. The resulting mixture was evaporated under reduced pressure. The residue was purified by reverse phase column 30 chromatography followed by treatment of 1N hydrochloric acid to give 6-[4-[2-[[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]amino]ethyl]phenyl]-1-isopropyl-N-(methyl sulfonyl)-1H-indole-3-carboxamide hydrochloride (81 mg). NMR (200 MHz, DMSO-d 6 , 8): 1.52 (6H, d, J=6.5Hz), 35 3.00-3.45 (6H, m), 3.39 (3H, s), 4.90-5.10 (2H, WO 2006/033446 PCT/JP2005/017669 85 m), 7.30-7.60 (7H, m), 7.76 (2H, d, J=8.2Hz), 7.91 (1H, s), 8.19 (1H, d, J=8.3Hz), 8.65 (lH, s) (-)ESI-MS (m/z): 552 (M-HCl-H)~ 5 Preparation 65 The following compound was obtained according to a similar manner to that of Preparation 43. 10, Methyl 4'-[2-[(tert-butoxycarbonyl)[(2R)-2-phenyl-2 (tetrahydro-2H-pyran-2-yloxy)ethyl] aminolethyl] -3 (isopropylthio)-4-biphenylcarboxylate (+)ESI-MS (m/z): 656 (M+Na)+ 15 Preparation 66 The following compound was obtained according to a similar manner to that of Example 2. Methyl 4'-[2-[(tert-butoxycarbonyl)amino]ethyl]-3 20 (cyclohexyloxy-) -4-biphenylcarboxylate (+)ESI-MS (m/z): 454 (M+H)+ Preparation 67 The following compound was obtained according to a 25 similar manner to that of Preparation 3. 4'-[2-[(tert-Butoxycarbonyl)[(2R)-2-phenyl-2 (tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3 (isopropylthio)-4-biphenylcarboxylic acid 30 (-)ESI-MS (m/z): 618 (M-H)~ Preparation 68 To a solution of methyl 4'-[2-[(tert-butoxycarbonyl) [(2R)-2-(6-cloro-3-pyridyl)-2-hydroxyethyl]aminoJethyl]-3 35 (cyclohexyloxy)-4-biphenylcarboxylate (1.43 g) in WO 2006/033446 PCT/JP2005/017669 86 dichloromethane (25 ml) were added 3,4-dihydro-2H-pyran (0.64 ml) and pyridinium p-toluenesulfonate (118 mg) at room temperature and the mixture was stirred for 2 days under nitrogen. The mixture was diluted with ethyl 5 acetate, washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to give residue (2.34 g). To a solution of the above residue in methanol (8 ml)/tetrahydrofuran (8 ml) was added aqueous solution of sodium hydroxide (1N, 8 ml) at room 10 temperature and the mixture was stirred at room temperature overnight. The mixture solution was acidified with aqueous hydrochloric acid solution (1N), poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and 15 evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=6/4) to give 4'-[2-[(tert butoxycarbonyl)[(2R)-2-(6-chloro-3-pyridyl)-2-(tetrahydro 2H-pyran-2-yloxy)ethyl]amino]ethyl]-3-(cyclohexyloxy)-4 20 biphenylcarboxylic acid (1.42 g). (-)ESI-MS (m/z): 677 (M-H)~ Preparation 69 To a solution of 4'-[2-[(tert-butoxycarbonyl)[(2R)-2 25 phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl] 3-isopropoxy-4-biphenylcarboxylic acid (224 mg) in N,N dimethylformamide (2 ml) was added 1,1'-carbonyldi imidazole (72 mg) at room temperature and the mixture was stirred at the same temperature for 1 hour. 1-Pentane 30 sulfonamide (67 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.067 ml) were added to the mixture at room temperature. The mixture was stirred at 70 0 C for 4 hours. After cooling down to room temperature, the mixture was diluted with ethyl acetate, washed with aqueous hydrochloric acid 35 solution (0.5N) and brine, dried over sodium sulfate and WO 2006/033446 PCT/JP2005/017669 87 evaporated under reduced pressure to give residue '(403 mg). To a solution of the above residue in methanol (2 ml) was added 4-methylbenzenesulfonic acid at room temperature and the mixture was stirred at the same temperature for 2 days. 5 The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate =7/3) to give tert-butyl [(2R)-2-hydroxy-2-phenylethyl] 10 [2-[3'-isopropoxy-4'-[[(pentylsulfonyl)amino]carbonyl]-4 biphenylyl]ethyl]carbamate (179 mg). (+)ESI-MS (m/z): 675 (M+Na)+ Preparation 70 15 The following compounds were.obtained according to a similar manner to that of Preparation 69. (1) tert-Butyl [(2R)-2-hydroxy-2-phenylethyl][2-[4' [[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3' 20 isopropoxy-4-biphenylyl]ethyl]carbamate (+)ESI-MS.(m/z): 663 (M+Na)+ (2) tert-Butyl [(2R)-2-hydroxy-2-phenylethyl][2-[4' [[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3' 25 (isopropylthio)-4-biphenylyl]ethyl]carbamate (+)ESI-MS (m/z): 679 (M+Na)+ '(3) tert-Butyl [2-[3'-(cyclohexyloxy)-4'-[[[(3 hydroxypropyl)sulfonyl]amino]carbonyl]-4-biphenylyl] 30 ethyl][(2R)-2-hydroxy-2-phenylethyl]carbamate (+)ESI-MS (m/z): 703 (M+Na)+ (4) tert-Butyl [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxy ethyl][2-[3'-(cyclohexyloxy)-4'-[[[(3-hydroxypropyl) 35 sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl]carbamate WO 2006/033446 PCT/JP2005/017669 88 (+)ESI-MS (m/z): 716 (M+H)+ (5) tert-Butyl [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxy ethyl][2-[3'-(cyclohexyloxy)-4'-[[[(2-methoxyethyl) 5 sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl]carbamate. (+)ESI-MS (m/z): 716 (M+H)+ Preparation 71 To a solution of methyl 4'-[2-[(tert-butoxycarbonyl) 10 amino]ethyl]-3-(cyclohexyloxy)-4-.biphenylcarboxylate (1.52 g) in 1,4-dioxane (6 ml) was added hydrochloric acid 1,4 dioxane solution (4N, 8 ml) at room temperature and the mixture was stirred overnight. The.mixture was evaporated under reduced pressure. The residue was dissolved in 15 chloroform/methanol (5/1, 80 ml). The solution was washed with aqueous sodium bicarbonate solution (80 ml) and brine, dried over sodium sulfate and evaporated under reduced pressure. A mixture of the above residue (1.18 g) and N,N'-bis(trimethylsilyl)urea (0.85 g) in dimethyl 20 sulfoxide (6 ml) was stirred at 65'C under nitrogen atmosphere. After 1 hour stirring, 2-chloro-5-[(2R)-2 oxiranyllpyridine (0.65 g) was added to the mixture. The mixture was stirred at 65 0 C for 40 hours. Conc. aqueous hydrochloric acid solution (0.4 ml) was added to the 25 mixture at approximately 0 0 C. The mixture was stirred at room temperature for 30 minutes. Aqueous sodium bicarbonate solution (40 ml) was added into the mixture. The mixture was extracted with chloroform, dried over sodium sulfate and evaporated under reduced pressure. The 30 mixture of the above residue (2.3 g) and di-tert-butyl dicarbonate (1.3 g) in tetrahydrofuran (5 ml) was stirred overnight. The mixture was poured into water, extracted with ethyl acetate, dried over sodium sulfate and evaporated under reduced pressure. The residue was 35 purified by column chromatography on silica gel WO 2006/033446 PCT/JP2005/017669 89 (hexane/ethyl acetate=5/5) to give methyl 4'-[2-[(tert butoxycarbonyl)['(2R)-2-(6-chloro-3-pyridyl)-2-hydroxy ethyl)amino]ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylate (1.44 g). 5 (+)ESI-MS (m/z): 609 (M+H)+ Preparation 72 The mixture of tert-butyl [(2R)-2-(6-chloro-3 pyridyl)-2-hydroxyethyl][2-[3'-(cyclohexyloxy)-4'-[[[( 3 10 hydroxypropyl)sulfonyl]amino]carbonyl]-4 -biphenylyl] ethyl]carbamate (145 mg), ammonium formate (128 mg) and palladium on carbon powder (50 mg) in methanol (2 ml) and water (0.2 ml) was refluxed for 50 minutes. The catalyst was filtered off and the filtrate was evaporated under 15 reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=94/6) to give tert-butyl [2-[3'-(cyclohexyloxy)-4'-[[[(3-hydroxy propyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl][(2R) 2-hydroxy-2-(3-pyridyl)ethyl]carbamate (117 mg). 20 (+)ESI-MS (m/z): 682 (M+H)+ Preparation 73 The following compound was obtained according to a similar manner to that of Preparation 72. 25 tert-Butyl [2-[3'-(cyclohexyloxy)-4'-[[[(2-methoxy ethyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl][(2R)-2 hydroxy-2-(3-pyridyl)ethyl]carbamate (+)ESI-MS (m/z): 682 (M+H)+ 30 Example 36 A mixture of tert-butyl [2-[3'-(isopropylthio)-4' [[(3-pyridylsulfonyl)amino] carbonyl]-4-biphenylyl] ethyl][(2R)-'2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy) 35 ethyl]carbamate (411 mg) and hydrogen chloride in methanol WO 2006/033446 PCT/JP2005/017669 90 (10%, 8.22 ml) was stirred at room temperature overnight. The mixture was evaporated and recrystallized from ethanol to give 4'-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino] ethyl]-3-(isopropylthio)-N-(3-pyridylsulfonyl)-4 5 biphenylcarboxamide dihydrochloride (242 mg). NMR (200 MHz, DMSO-d 6 , 8): 1.05 (6H, d, J=6.6Hz), 2.89-3.33 (6H, m), 3.33-3.46 (1H, m), 5.00 (1H, dd, J=2.7, 10.3Hz), 7.30-7.41 (7H, m), 7.54-7.64 (2H, m), 7.68-7.79 (4H, m), 8.41 (1H', dt, J=2.3, 10 4Hz), 8.94 (1H, dd, J=1.5, 5Hz), 8.93 (1H, br s), 9.15 (1H, d, J=1.5Hz), 9.33 (1H, br s) (-)ESI-MS (m/z): 574 (M-H)~ The following compounds from Example 37 to Example 39 15 were obtained according to a similar manner to that of Example 36. Example 37 N-[(Cyanomethyl)sulfonyl]-4'-[2-[[(2R)-2-hydroxy-2 phenylethyllamino]ethyl] -3- (isopropylthio) -4-biphenyl 20 carboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.27 (6H, d, J=6.5Hz), 3.05-3.24 (6H, m), 3.60-3.73 (1H, m), 4.86 (2H, s), 4.98 (1H, d, J=9.5Hz), 6.22 (1H, br s), 7.31-7.42 (7H, m), 7..52 (1H, d, J=8Hz), 7.62 25 7.63 (1H, m), 7.69-7.76 (3H, m), 8.85 (1H, br s), 9.06 (1H, br s) (-)ESI-MS (m/z): 536 (M-H)~ Example 38 3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2-( 3 30 pyridyl)ethyl]amino]ethyl]-N-(3-pyridylsulfonyl)-4 biphenylcarboxamide trihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.31-1.67 (8H, m), 1.71 1.91 (2H, m), 3.02-3.50 (6H, m), 4.61-4i78 (1H, m), 5.34 (1H, d, J=5.6Hz),. 7.29 (1H, d, J=8Hz), 35 7.36-7.40 (3H, m), 7.54 (1H, d, J=8Hz), 7.70 (2H, WO 2006/033446 PCT/JP2005/017669 91 d, J=8Hz ), 7.74 (1H, dd, J=6.2, 10.5Hz), 8.08 (1H, dd, J=5.5, 8Hz), 8.41 (1H, dt, J=2.8, 3.8Hz), 8.60 (1H, d, J=8Hz),' 8.88-8.94 (3H, m), 9.15 (1H, d, J=1.5Hz), 9.36 (2H, br s), 12.06 5 (1H, br s) (-)ESI-MS (m/z): 599 (M-H)~ Example 39 N-[(Cyanomethyl)sulfonyl]-3-(cyclohexyloxy)-4'-[2 [[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4 10 biphenylcarboxamide dihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.32-1.85 (8H, m), 1.86 2.02 (2H,' m), 3.04-3.48 .(6H, m), 4.63-4.91 (1H, m), 5.20-5.32 (3H, m), 7.34-7.42 (3H, m), 7.67 (1H, .d, J=8Hz), 7.74 (2H, d, J=8Hz), 8.00 (1H, 15 dd, J=5.5, 8Hz), 8.50 (1H, d, J=8.5Hz), 8.85 (1H, d, J=5.5Hz), 8.91 (1H, s), 9.28 (1H, br s), 9.39 (1H, br s) (-)ESI-MS (m/z): 561 (M-H)~ 20 Example 40 To a solution of 4'-[[2-[(tert-butoxycarbonyl)[(2R) 2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-3 isobutoxy-4-biphenylcarboxylic acid (60.0 mg) in N,N dimethylformamide (0.450 ml) was added 1,l'-carbonylbis 25 1H-imidazole (18.3 mg) and the mixture was stirred at room temperature for 1.5 hours under nitrogen atmosphere. To the mixture were added 2,3,4,6,7,8,9,10-octahydropyrimido [1,2-a]azepine (0.0185 ml) and a solution of 3-(amino sulfonyl)propyl acetate (22.4 mg) in N,N-dimethylformamide 30 (0.300 ml) and the mixture was stirred at room temperature for 2 days. The reaction mixture was warmed to 120 0 C and stirred at the same temperature for 2 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, washed with water and brine 35 and dried over, magnesium sulfate. Filtration followed by WO 2006/033446 PCT/JP2005/017669 92 evaporation gave the crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/3 to 1/1) to give 3-[[[[4'-[[2-[(tert-butoxy carbonyl) [(2R) -2- (3- chlorophenyl) -2-hydroxyethyl ] amino] 5 ethyl]amino]-3-isobutoxy-4-biphenylylcarbonyl]amino] sulfonyllpropyl acetate (34.1 mg) as a yellow paste. (-)ESI-MS (m/z): 744 (M-H)~ Example 41 10 To a solution of 3-[[[[4'-[[2-[(tert-butoxycarbonyl) [(2R) -2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl] amino]-3-isobutoxy-4-biphenylyl]carbonyl]amino]sulfonyl] propyl acetate (34.0 mg) in methanol (0.340 ml) and tetrahydrofuran (0.170 ml) was added 1N aqueous sodium 15 hydroxide solution (0.228 ml) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, washed with water and brine and dried over magnesium sulfate. The- solvent was concentrated under reduced pressure. To a solution of 20 the resulting residue in 1,4-dioxane (0.340 ml) was added 4N hydrogen chloride in 1,4-dioxane (0.340 ml) and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and to the residue was added ethyl acetate. The precipitate was 25 collected by filtration and dried in vacuo to give 4'-[[2 [[(2R) -2-(3-chlorophenyl) -2-hydroxyethyl]amino]ethyl] amino]-N-[(3-hydroxypropyl)sulfonyl]-3-isobutoxy-4 biphenylcarboxamide dihydrochloride (24.8 mg) as a yellow powder. 30 NMR (200 MHz, DMSO-d 6 , 8): 1.05 (6H, d, J=7Hz), 1.79 1.93 (2H, m), 2.02-2.19 (1H, m), 2.99-3.35 (4H, m), 3.61-3.44 (6H, m), 4.01-4.06 (2H, m), 4.98 5.05 (1H, m), 6.75 (2H, d, J=8.5Hz), 7.28-7.49 (6H, m), 7.57-7.71 (3H, m), 8.85 (1H, br s), 35 9.18 (1H, br s), 10.99 (1H, s) WO 2006/033446 PCT/JP2005/017669 93 (-)ESI-MS (m/z): 603 (M-H)~ Example 42 The following compound was, obtained according to a 5 similar manner to that of Example 40. 3- [[[[4'- [[2- [ (tert-Butoxycarbonyl) [(2R) -2-.(3 chlorophenyl) -2-hydroxyethyl3amino] ethyl]amino] -3 (cyclohexyloxy)-4-biphenylyl]carbonyl]amino]sulfonyl] 10 propyl acetate (-)ESI-MS-(m/z): 770 (M-H)~ Example 43 The following compound was obtained according to a 15 similar manner to that of Example 41. 4'-[[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl]amino]-3-(cyclohexyloxy)-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide dihydrochloride 20 NMR (200 MHz, DMSO-d 6 , 5): 1.29-1.64 (6H, m), 1.68.

1.78 (2H, m), 1.82-1.91 (2H, m), 1.93-2.01 (2H, m), 3.02-3.31 (4H, m), 3.48-3.58 (6H, m), 4.80 4.86 (1H, m), 5.01-5.04 (1H, m), 6.76 (2H, d, J=8.8Hz), 7.29-7.48 .(6H, m), 7.58 (2H, d, 25 J=8.8Hz); 7.74 (1H, d, J=8.4Hz), 8.87 (1H, br s), 9.24 (1H, br s), 10.97 (1H, s) (-)ESI-MS (m/z): 628 (M-H)~ Example 44 30 The following compound was obtained according to a similar manner to that of Preparation 64. 6-[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl]phenyl]-N-[(3-hydroxypropyl)sulfonyl]-1 35 isopropyl-1H-indole-3-carboxamide hydrochloride WO 2006/033446 PCT/JP2005/017669 94 NMR (200 MHz, DMSO-d 6 , 5): 1.52 (6H, d, J=6.5Hz), 1.75-1.95 (2H, m), 2.95-3.65 (10H, m), 4.90-5.05 (2H, m), 7.30-7.60 (7H, m), 7.76 (2H, d, J=8.2Hz); 7.90 (iH, s), 8.18 (1H, d, J=8.4Hz), 5 8.65 (1H, s) (-)ESI-MS (mfz): 596 (M-2HCl-H)~ Example 45 To 3-[[[[4'-[2-[(tert-Butoxycarbonyl)[(2R-)-2-[[tert 10 butyl(dimethyl)silyl]oxy]-2-(3-pyridyl)ethyl]amino]ethyl] 3-(cyclohexyloxy)-4-biphenylyl]carbonyl amino]sulfonyl] propionic- acid (49.7 mg) was added 4Nhydrogen chloride in 1,4-dioxane (1.5 ml). After stirring at room temperature for 12 hours, the mixture was evaporated to give 3-[[1[3 15 (cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2-(3-pyridyl) ethyl]amino]ethyl]-4-biphenylyl]carbonyl]amino]sulfonyl] propanoic acid dihydrochloride (41.0 mg). NMR (200 MHz, DMSO-d 6 , 8): 1.23-1.70 (10H, m), 1.90 1.98 (2H, m), 2.71-2.79 (2H, m), 3.07-3.36 (4H, 20 m), 3.56-3.79 (2H, m), 5.20-5.29 (1H, m), 5.70 5.76 (1H, m), 6.30 (1H, br s), 7.16-7.41 (4H, m), 7.63-7.75 (3H, m), 7.90-7.97 (1H, m), 8.41-8.46 (1H, m), 8.84 (2H, d, J=16Hz), 9.20-9.34 (2H, m) (-)ESI-MS (m/z): 594 (M-2HCl-H)~ 25 The following compounds from Example 46 to Example 49 were obtained according to a similar manner to that of Example 45. Example 46 30 3-(Cyclohexyloxy)-N-[(3-hydroxy-3-methylbutyl) sulfonyl]-4'-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl] amino]ethyl]-4-biphenylcarboxamide dihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.12 (6H, s), 1.12-1.92 (10H, m), 1.92-1.98 (2H, m), 3.07-3.59 (8H, m), 35 4.78-4.83 (1H, m), 5.20-5.28 (1H, m), 7.33-7.44 WO 2006/033446 PCT/JP2005/017669 95 (4H, m), 7.72-7.76 (3H, m)', 7.88-7.95 (1H, m), 8.30-8.42-(lH, m), 8.75-8.86 (2H, m) (-)ESI-MS (m/z.): 608 (M-H)~ Example 47 5 N-[(2-Amino-2-oxoethyl)sulfonyl]-3-(cyclohexyloxy) 4'-[2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]aminoethyl]- 4 biphenylcarboxamide dihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.39-1.72 (10H, m), 2.99 (2H, s), 3.00-3.50 (6H, m), 4.70-4.90 (1H, m), 10 5.25-5.30 (1H, m), 7.23-7.44 (4H, m), 7.73-7.97 (4H, m), 8.40-8.45 (1H, m), 8.81-8.88 (2H, m), 9.24-9.40 (2H, m) (-)ESI-MS (m/z): 579 (M-H)~ Example 48 15 3-(Cyclohexyloxy)-N-[(4-hydroxybutyl)sulfonyl]-4'-[2 [[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4 biphenylcarboxamide dihydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.23-1.91 (14H, m), 3.11 3.80 (10H, m), 4.78-4.82 (1H, m), 5.23-5.27 (1H, 20 m), 7.30-7.42 (4H, m), 7.71-7.75 (3H, m), 7.86 7.93 (lH, m), 8.34-8.39 (lH, m), 8.78-8.86 (2H, m), 9.12-9.29 (2H, m), 11.17 (1H, s) (-)ESI-MS (m/z): 594 (M-H)~ Example 49 25 N-[(2-Amino-2-oxoethyl)sulfonyl]-4'-[2-[[(2R)- 2

-(

3 chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3 (cyclohexyloxy)-4-biphenylcarboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.02-1.94 (10H, m), 3.05 3.33 (6H, m), 4.35 (2H, s), 4-.81-4.83 (1H, m), 30 4.98-5.03, (lH, m), 6.36 (1H, d, J=2Hz), 7.36 7.48 (7H, m), 7.73-7.84 (4H, m), 8.90-9.13 (2H, m), 11.2 (1H, br s) (+)ESI-MS (m/z): 594 (M+H)+ 35 Example 50 WO 2006/033446 PCT/JP2005/017669 96 To a mixture of 4'-[2-[(tert-butoxydarbonyl)[(2R)-2 (6-chloro-3-pyridyl)-2-(tetrahydro-2H-pyran-2-yloxy) ethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylic acid (180 mg) in N,N-dimethylformamide (2 ml) was added 5 1,1'-carbonyldiimidazole (51.6 mg) at room temperature and. the mixture was stirred at the same temperature for 1 hour. N-Ethylsulfamide (46.1 mg) and 1,8-diazabicyclo[5.4.0] 7-undecene (0.056 ml) were added to the mixture at room temperature. The mixture was stirred at room temperature 10 for 0.5 hour and at 120 0 C for 16 hours. The mixture was diluted with ethyl acetate, and washed with water, 0.5N hydrochloric acid and brine, and dried over sodium sulfate and evaporated under reduced pressure to give residue (220 mg). To a mixture of the above residue in methanol (3 ml) 15 was added 4-methylbenzensulfonic acid (22 mg) at room temperature and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate,.and washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to 20 give the residue. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=50/50) to give the residue (135 mg). To a mixture of the above residue and ammonium formate (118 mg) in methanol (2 ml) and water (0.2 ml) was added 10% palladium on carbon (50% 25 wet, 25 mg) under nitrogen atmosphere. The mixture was refluxed for 30 minutes. The mixture was filtered through celite pad and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform/methanol=95/5) to give tert 30 butyl [2-[3'-(cyclohexyloxy)-4'-[[[(ethylamino)sulfonyl] amino]carbonyl]-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-(3 pyridyl)ethyl]carbamate (132 mg). (-)ESI-MS (m/z): 665 (M-H)~ 35 Example 51 WO 2006/033446 PCT/JP2005/017669 97 The following compound was obtained according to a similar manner to that of Example 41. 4'-[2-[[(2R)-2-(6-Chloro-3-pyridyl)-2-hydroxyethyl] 5 amino]ethyl]-3-(cyclohexyloxy)-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide hydrochloride NMR (200 MHz, DMSO-d 6 , 8): 1.29-2.03 (12H, m), 3.02 3.33 (6H, m), 3.48-3.60 (4H, m),.4.02-4.38 (2H, m), 4.75-4.87 (1H, m), 5.13 (1H, dd,' J=3.0, 10 9.5Hz), 7.33-7.42 (4H, m), 7.57 ( H, d, J=8.OHz ), 7.71-7.76 (3H, m), 7.89 (1H, d, J=2.5Hz), 8.46 (1H, d, J=2.5Hz), 9.09 (1H, br s), 9.35 (1H, br s), 11.18 (1U, s) (-)ESI-MS (m/z): 614 (M-H) 15 Example 52 To a solution of tert-butyl [2-[3'-(cyclohexyloxy) 4'-[[[(3-hydroxypropyl')sulfonyl]amino]carbonyl]-4 biphenylyl]ethyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl) 20 carbamate (110 mg) in 1,4-dioxane (1.5 ml) was added hydrogen chloride in 1,4-dioxane (4N, 1.5 ml) at room temperature and the mixture was stirred at the same temperature overnight. The mixture was evaporated under reduced pressure to give 3-(cyclohexyloxy)-N-[(3 25 hydroxypropyl)sulfonyl]-4'-[2-[[(2R)-2-hydroxy-2-(3 pyridyl)ethyl]amino]ethyl]-4-biphenylcarboxamide dihydrochloride (105 mg) as a white solid. NMR (200 MHz, DMSO-d 6 , 8): 1.35-2.02 (12H, m), 3.05 3.39 (6H, m), 3.48-3.60 (4H, m), 4.75-4.87 (1H, 30 m), 5.27-5.35 (1H, m), 7.33-7.44 (4H, m), 7.71 7.75 (3H, m), 7.98 (1H, dd, J=5.5, 8.5Hz), 8.49 (1H, d, J=8.5Hz), 8.83-8.91 (2H, m), 9.30 (1H, br s), 9.41 (1H, br s), 11.18 (1H, s) (-)ESI-MS (m/z): 580 (M-H)~ 35 WO 2006/033446 PCT/JP2005/017669 98 Example 53 To a solution of tert-butyl [2-[3'-(cyclohexyloxy) 4'-[[[(2-methoxyethyl)sulfonyl]amino]carbonyl]-4 biphenylyl] ethyl] [(2R) -2-hydroxy-2- (3 -pyridyl) ethyl] 5 carbamate (199 mg) in 1,4-dioxane (2.0 ml) was added hydrogen chloride in 1,4-dioxane (4N, 2.0 ml) at room temperature and the mixture was stirred at the same temperature 3 hours. The mixture was evaporated under reduced -pressure to give 3-(cyclohexyloxy)-4'-'[2-['[(2R)-2 10 hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-N-[(2-methoxy ethyl)sulfonyl]-4-biphenylcarboxamide dihydrochloride (153 mg) as a white solid. NMR (200 MHz, DMSO-d 6 , 8): 1.31-2.04 (10H, m), 3.04 3.50 (6H, m),-3.23 (3H, s), 3.72-3.84 (4H, m), 15 4.78-4.89 (1H, m), 5..27-5.37 (1H, m), 7.34-7.45 (4H, m), 7.68-7.79 (3H, m), 8.00 (1H, dd, J=5.5, 8.4Hz), 8.51 .(1H, d, J=8.4Hz), 8.83-8.92 (2H, m), 9.33 (1H, br s), 9.45 (1H, br s), 11.19 (1H, s) (-)ESI-MS (m/z): 580 (M-H)~ 20 Example 54 To a solution of tert-butyl [(2R)-2-hydroxy-2-phenyl ethyl][2-[4'-[[[(3-hydroxypopyl)sulfonyl] amino]carbonyl] 3'-(isopropylthio)-4-biphenylyl]ethyl]carbamate (94 mg) in 25 1,4-dioxane (1.5'ml) was added hydrogen chloride in 1,4 dioxane (4N, 1.5 ml) at room temperature and the mixture was stirred at the same temperature overnight. The mixture was evaporated under, reduced pressure to give 4' [2-[ [(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-N-[(3 30 hydroxypropyl)sulfonyl]-3-(isopropylthio)-4-biphenyl carboxamide hydrochloride (75 mg) as a white solid. NMR (200 MHz, DMSO-d 6 , 8): 1.25 (6H, d, J=6.5Hz), 1.85-1.99 (2H, m), 3.02-3.27 (6H, m), 3.49-3.58 (4H, m), 3.62-3.72 (1H, m), 4.76 (1H, br s), 35 4.95-5.04 (1H, m),-6.23 (1H, d, J=4Hz), 7.31- WO 2006/033446 PCT/JP2005/017669 99 7.42 (7H, m), 7.55-7.64 (2H, M), 7.70-7.74 (3H, m), 8.92 (1H, br s), 9.26 (1H, br s), 12.14 (1H, s) (-)ESI-MS (m/z): 555 (M-H)~ 5 Example 55 To a solution of 3-(cyclohexyloxy)-N-[(3-hydroxy propyl)sulfonyl] -4'- [2- [ [ (2R) -2-hydroxy-2- (3-pyridyl) ethyl]amino]ethyl]-4-biphenylcarboxamide dihydrochloride 10 (1.2 g) in water (5 ml) was added 1N sodium hydroxide aqueous solution (3.7 ml). The obtained solid was filtrated and then followed by crystallization from isopropyl alcohol to give 3-(cyclohexyloxy)-N-[(3 hydroxypropyl)sulfonylI]-4'-[2-[[(2R)-2-hydroxy-2-(3 15 pyridyl)ethyl]amino]ethyl]-4-biphenylcarboxamide (1.0 g). NMR (200 MHz, DMSO-d 6 , 8): 1.30-2.00 (12H, m), 2.80 3.10 (6H, m), 3.40-3.60 (4H, m), 4.51' (1H, m), 4.85 (1H, m), 7.10-7.40 (5H, m), 7.48 (1H, d, J=8Hz), 7.60 (1H, d, J=8Hz), 7.76 (1H, d, 20 J=8Hz), 8.47 (1H, m), 8.57 (1H, s) (+)ESI-MS (m/z): 582 (M+H)+ Example 56 The following compound was obtained according to a 25 similar manner to that of Example 55. 3-(Cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4' [3-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-4 biphenylcarboxamide 30 NMR (200 MHz, DMSO-d 6 , b): 1.30-2.00 (14H, m), 2.80 3.60 (10H, m), 4.53 (1H, m), 4.87 (1H, m), 7.10 7.40 (5H, m), 7.49 (1H, d, J=8Hz), 7.60 (1H, d, J=8Hz), 7.79 (1H, d, J=8Hz), 8.47 (1H, m), 8.57 (1H, s) 35 (+)ESI-MS (m/z): 596 (M+H)+ C:\NRPorbl\DC SZP\440663_ I .DOC-3 1012 I I - 99A Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or 5 steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general 10 knowledge in the field of endeavour to which this specification relates.

Claims (2)

1. A compound of the formula [I]: OH R 3 5 R1 N R 7 A X--G/ R8 R 2 10 wherein N A is or 7N

15.N ~G is or R 6 20 -X- is R5 Y in which -Y- is bond, -0-, -NH- or -CH 2 -~, and R 4 , R 5 and R6 are each independently hydrogen, lower alkyl or 25 hydroxy(lower)alkyl, or CH 2 n in which n is 0, 1 or 2, 30 RI is hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, aryloxy, nitro, amino, (mono or di) (lower)alkylamino or arylamino, R2 is hydrogen, lower alkyl or hydroxy(lower)alkyl, R3 is hydrogen or an amino protective group, 35 R7 is hydrogen, lower alkyl, cyclo(lower)alkyl, lower WO 2006/033446 PCT/JP2005/017669 101 alkenyl, -Z-R 9 or -N , in which -Z- is -0-, R9 -S-, -SO- or -SO2-, and each R9 is independently hydrogen, lower 5 alkyl, cyclo(lower)alkyl, lower alkenyl, carbamoyl, lower alkylcarbamoyl, lower alkylsulfonyl, aryl or a heterocyclic group, and R 8 is -D-E-R 10 , in which -D- is -CONHSO 2 - or -SO 2 NHCO-, 10 E is bond or lower alkylene, and R1 0 -is halogen,-cyano, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, .a heterocyclic group, Ril 15 -O-R 11 , -S-R 11 or -N , in which Ril each R11 is independently hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or 20 aryl (lower) alkyl, or a prodrug thereof or a salt thereof. 2. A compound of claim 1, wherein 25R6 -X- is Y , in which -Y- is bond, -0-, -NH- or -CH 2 -, and R 4 , R 5 and R6 are each independently 30 hydrogen, lower alkyl or hydroxy(lower)alkyl. 3. A compound of claim 2, wherein Rl is hydrogen, halogen, nitro or amino, 35 R2 is hydrogen or lower alkyl, WO 2006/033446 PCT/JP2005/017669 102 R 3 is hydrogen, R7 is hydrogen, lower alkyl, cyclo(lower)alkyl, -Z-R 9 or -N , in which -Z- is -0-, -S-, -SO-- or 5 R 9 -S02-, and each R 9 is independently hydrogen, lower alkyl or cyclo(lower)alkyl, and R 8 is -D-E-R 10 , in which -D- is -CONHSO 2 - or -SO 2 NHCO-, 10 -E is bond or lower alkylene, and R10 is halogen, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, pyridyl, R 1 1 -- R or -N , in which each R is 15 "R11 15 independently hydrogen, lower alkyl, lower alkanoyl or lower alkoxycarbonyl. 20 4. A compound of claim 3, wherein R 6 -X- is R y / 0, in which -Y- is bond, -0-, 25 -NH- or -CH 2 -, and R 4 , R 5 and R6 are each hydrogen, R 7 is lower alkyl, cyclo(lower)alkyl, -Z-R 9 'or H N , in which -Z- is -0- or -S-, and 30R each R9 is independently lower alkyl or cyclo(lower)alkyl, and R8 is -D-E-R 10 , in which -D- is -CONHSO 2 - or -SO 2 NHCO-, E is bond or lower alkylene, and 35 R 10 is cyano, carboxy, carbamoyl, pyridyl, WO 2006/033446 PCT/JP2005/017669 103 -- R or -N , in which each R 11 is R11 independently hydrogen or lower 5 alkyl. 5. A compound of claim 4, which is selected from a group of (1) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-N 10 [(3-hydroxypropyl)sulfonyl]-3-isopropoxy-4-biphenyl carboxamide, (2) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]amino]ethyl]-N [(3-hydroxypropyl)sulfonyl]-3-(isopropylthio)-4 biphenylcarboxamide, 15 (3) 3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2-phenyl ethyl]amino]ethyl]-N-[(3-hydroxypropyl)sulfonyl]-4 biphenylcarboxamide, (4) 3-(Cyclohexyloxy)-N-[(3-hydroxypropyl)-sulfonyl]-4' [2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl] 20 4-biphenylcarboxamide, (5) 3-(Cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4'-[2 [[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-4 biphenylcarboxamide, (6) N-[(3-Hydroxypropyl)sulfonyl]-4'-[2-[[(2R)-2-hydroxy 25 2-(3-pyridyl)ethyl]amino]ethyl]-3-isopropoxy- 4 biphenylcarboxamide, (7) 3-(Cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4'-[2 [[(2R) -2-hydroxy-2-phenylethyl ]amino]ethyl] -4 biphenylcarboxamide, 30 (8) N-[(3-Hydroxypropyl)sulfonyl]-4'-[2-[[(2R)-2-hydroxy 2-(3-pyridyl)ethyl]amino]ethyl]-3-propoxy-4-biphenyl carboxamide, (9) 3-Cyclopentyl-4'-[2-[[(2R)-2-hydroxy-2-phenylethyl] amino ]ethoxy] -N- [ (3-hydroxypropyl) sulfonyl] -4 35 biphenylcarboxamide, WO 2006/033446 PCT/JP2005/017669 104 (10) 4'-[2-[[(2R)-2-(4-Aminophenyl)-2-hydroxyethyl]aminol] ethyl]-N-[(3-hydroxypropyl)sulfonyl]-3-isobutyl- 4 biphenylcarboxamide, (11) 4'-[2-[[(2R)-2-(4-Aminophenyl)-2-hydroxyethyl]amino] 5 ethoxy]-3-(cyclohexyloxy)-N-[(3-hydroxypropyl) sulfonyl]-4-biphenylcarboxamide, (12) 3-(Cycloheptyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4' [2-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl] 4-biphenylcarboxamide, 10 (13) 3-(Cyclohexyloxy)-N-[(2-hydroxyethyl)sulfonyl]-4'-[2 [[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]amino] ethyl]-4-biphenylcarboxamide, (14) 3-(Cyclohexyloxy)-N-[(ethylamino)sulfonyl]-4'-[2 [[(2R)-2-hydroxy-2-(3-pyridyl)ethylamino]ethyl]-4 15 biphenylcarboxamide, (15) 3-(Cyclohexylamino)-4'-[2-[[(2R)-2-hydroxy-2-phenyl ethyl]amino]ethoxy]-N-[(3-hydroxypropyl)sulfonyl]-4 biphenylcarboxamide, (16) 3-(Cyclohexyloxy)-N-[(3-hydroxypropyl)sulfonyl]-4' 20 [3-[[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl] 4-biphenylcarboxamide, (17) N-[(3-Hydroxypropyl)sulfonyl]-4'-[3-[[(2R)-2-hydroxy 2-(3-pyridyl)ethylaminol]propyl]-3-isobutoxy-4 biphenylcarboxamide, 25 (18) 4-Amino-N-[[-(cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy 2-phenylethyl]amino]ethyl]-4-biphenylyl]sulfonyl] butanamide, (19) 2-Amino-N-[[3-(cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy 2-phenylethyl]amino]ethyl]-4-biphenylyl]sulfonyl] 30 acetamide, (20) 3-(Cyclohexyloxy) -N-[(3-hydroxy-3-methylbutyl) sulfonyl]-4'-[2-[[(2R)-2-hydroxy-2-phenylethyl] amino]ethyl]-4-biphenylcarboxamide, (21) N-[(3-Amino-3-oxopropyl)sulfonyl]-3-(cyclohexyloxy) 35 4'-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-4- 105 biphenylcarboxamide, (22) 3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-(3-fluorophenyl)-2 hydroxyethyl]amino]ethyl]-N-[(3-hydroxypropyl) sulfonyl] -4-biphenylcarboxamide, 5 (23) 4'-[2-[[(2R)-2-Hydroxy-2-phenylethyl]aminolethyl]-3 (isopropylthio)-N-(3-pyridylsulfonyl)-4-biphenyl carboxamide, (24) N-[(Cyanomethyl) sulfonyl]-4'-[2-[[(2R)--2-hydroxy-2 phenylethyl ]amino ]ethyl] -3- (isopropylthio) -4 10 biphenylcarboxamide, (25) 4'-[[2-[ [(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] amino]ethyl]amino]-N-[(3-hydroxypropyl)sulfonyl]-3 isobutoxy-4 -biphenylcarboxamide, (26) 6-[4-[2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl] 15 amino]ethyl]phenyl] -N-[ (3-hydroxypropyl)sulfonyl] -1 isopropyl-1H-indole-3-carboxamide., and (27) 3-[[[[3-(Cyclohexyloxy)-4'-[2-[[(2R)-2-hydroxy-2-(3 pyridyl) ethyl]amino ]ethyl] -4-biphenylyl]carbonyl] amino] sulfonyl]propanoic acid, 20 or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition which comprises, as an active ingredient, a compound of any one of claims I to 5 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients. 7. Use of a compound of any one of claims I to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. 8. A compound of any one of claims I to 5 or a pharmaceutically acceptable salt thereof for use as a medicament. 9. A compound of any one of claims 1 to 5 or a pharmaceutically salt thereof for use CANRPorbIDCC'JXT\344076 1.DOC-3lm1l/2011 - 106 as a p 3 adrenergic receptor agonist. 10. A method for the prophylactic and/or the therapeutic treatment of gastro-intestinal disorders, ulcer, overactive bladder, micturition disorders, pancreatitis, obesity or diabetes 5 which comprises administering a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof to a human being or an animal. 11. Use of a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylactic and/or the 10 therapeutic treatment of gastro-intestinal disorders, ulcer, overactive bladder, micturition disorders, pancreatitis, obesity or diabetes. 12. A compound of claim 1, substantially as hereinbefore described with reference to any one of the examples.